EP4642911A2 - Zusammensetzungen und verfahren zur regulierung von mapt - Google Patents

Zusammensetzungen und verfahren zur regulierung von mapt

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Publication number
EP4642911A2
EP4642911A2 EP23855770.6A EP23855770A EP4642911A2 EP 4642911 A2 EP4642911 A2 EP 4642911A2 EP 23855770 A EP23855770 A EP 23855770A EP 4642911 A2 EP4642911 A2 EP 4642911A2
Authority
EP
European Patent Office
Prior art keywords
nucleotide sequence
seq
sequence
relative
antisense strand
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23855770.6A
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English (en)
French (fr)
Inventor
Dinah Wen-Yee Sah
Kathrin HULTSCH
Jochen DECKERT
Wen Jin
Jinzhao Hou
Wencheng LIU
Todd Carter
Cansu COLPAN
Elisabeth KNOLL
Shiron Jessie LEE
Rajeev Nambiar SIVASANKARAN
Hechen BAO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Voyager Therapeutics Inc
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Voyager Therapeutics Inc
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Filing date
Publication date
Application filed by Voyager Therapeutics Inc filed Critical Voyager Therapeutics Inc
Publication of EP4642911A2 publication Critical patent/EP4642911A2/de
Pending legal-status Critical Current

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    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
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    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
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Definitions

  • the present disclosure relates generally to compositions and methods for vectorized delivery' of an agent, e.g., an RNA agent, that that inhibits a mutant, variant, or wild type human microtubule-associated protein tau (MAPT) gene, mRNA, and/or protein.
  • an agent e.g., an RNA agent, that that inhibits a mutant, variant, or wild type human microtubule-associated protein tau (MAPT) gene, mRNA, and/or protein.
  • MTT human microtubule-associated protein tau
  • Tauopathies which may also be referred to herein as tau-associated diseases, are a heterogeneous group of neurodegenerative diseases characterized by the dysfunction and/or aggregation of the microtubule- associated protein tau (MAPT) which may also be referred to as Tau herein, which is encoded by the MAPT gene.
  • MAPT microtubule-associated protein tau
  • Tau is normally a very soluble protein known to associate with microtubules based on the extent of its phosphory lation.
  • tauopathies tau becomes hyperphosphory lated, misfolds and aggregates as neurofibrillary tangles (NFT) of paired helical filaments (PHF), twisted ribbons or straight filaments.
  • NFT neurofibrillary tangles
  • PHF paired helical filaments
  • the present disclosure provides AAV particles encoding an agent for targeting MAPT, e.g., an RNA agent to modulate, e.g., inhibit, MAPT gene expression and/or MAPT protein production and methods of use thereof.
  • the agent for targeting MAPT e.g., a MAPT gene, mRNA, or protein (e.g., a tau protein) is an RNA agent for targeting MAPT, e.g., a siRNA duplex for targeting MAPT.
  • the agent for targeting MAPT comprises a modulatory polynucleotide encoding a siRNA duplex for targeting MAPT.
  • Methods for treating diseases associated MAPT expression e.g.. aberrant expression, such as tauopathies. including but not limited to Alzheimer’s disease (AD), frontotemporal dementia (FTD), and/or Dravet syndrome (DS) in a subject in need thereof.
  • AD Alzheimer’s disease
  • FDD frontotemporal dementia
  • DS Dravet syndrome
  • the present disclosure provides a short interfering ribonucleic acid (siRNA) for inhibiting expression of microtubule -associated protein tau (MAPT) which comprises a sense strand sequence and an antisense strand sequence, wherein the antisense sequence is complementary to at least 15. 16. 17, 18, 19, 20, or 21 contiguous nucleotides comprising 0, 1, 2. or 3 mismatches of a MAPT sequence comprising the nucleotide sequence of SEQ ID NO: 5024 or a nucleotide sequence provided in Table 3 or 19.
  • siRNA short interfering ribonucleic acid
  • MTT microtubule -associated protein tau
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Tables 3 4, 5, 9A, or 9B; and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1. or 0 nucleotides from any one of the sense strand sequences provided in Tables 3 4, 5, 9A. or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides from any one of the antisense strand sequences provided in Tables 3 4, 5, 9A, or 9B; and the sense strand sequence comprises at least 15, 16, 17, 18. 19, 20, 21 contiguous nucleotides from any one of the sense strand sequences provided in Tables 3 4, 5. 9A. or 9B, wherein the sense strand sequence and tire antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.
  • the antisense strand sequence comprises nucleotide sequence of any one of the antisense strand sequences provided in Tables 3 4, 5, 9A, or 9B; and the sense strand sequence comprises the nucleotide sequence of any one of the sense strand sequences provided in Tables 3 4, 5, 9A, or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.
  • the present disclosure provides a short interfering ribonucleic acid (siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) which comprises a sense strand sequence and an antisense strand sequence, wherein: (i) the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of any one of SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104, or 5128; and (ii) the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006, 4918.
  • siRNA short interfering ribonucleic acid
  • the present disclosure provides an adeno-associated virus (AAV) viral genome comprising a nucleotide sequence positioned between two inverted terminal repeats (ITRs), wherein the nucleotide sequence encodes an siRNA for inhibiting MAPT, wherein the siRNA comprises a sense strand sequence and an antisense strand sequence, wherein: (i) the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104, or 5128; and (ii) the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986.
  • AAV adeno-associated virus
  • the present disclosure provides a modulatory polynucleotide encoding an siRNA for targeting MAPT described herein.
  • the modulatory polynucleotide further comprises a 5’ flanking region, a loop region, and/or a 3’ flanking region.
  • the present disclosure provides an AAV particle comprising a promoter operably linked a nucleic acid encoding a modulatory polynucleotide comprising an siRNA for targeting MAPT described herein.
  • the present disclosure provides a method of making an AAV particle comprising an AAV capsid protein, e.g., an AAV capsid variant, encoding an siRNA for targeting MAPT described herein.
  • the method comprises providing a host cell comprising a viral genome encoding an siRNA described herein and incubating the host cell under conditions suitable to enclose the viral genome in the AAV capsid protein, e.g., an AAV capsid variant, thereby making the AAV particle.
  • the present disclosure provides a method of delivering an siRNA for inhibiting MAPT to a cell.
  • the method comprises administering an effective amount of an siRNA or an AAV particle encoding an siRNA described herein.
  • the present disclosure provides, a method of treating a subject having or diagnosed with having a genetic disorder e.g., a monogenic disorder or a polygenic disorder.
  • Tire method comprising administering an effective amount of an siRNA or an AAV particle encoding an siRNA described herein.
  • the present disclosure provides, a method of treating a subject having or diagnosed with having a neurological disorder e.g., a neurodegenerative disorder. The method comprising administering an effective amount of an siRNA or an AAV particle encoding an siRNA described herein.
  • a neurological disorder e.g., a neurodegenerative disorder.
  • the method comprising administering an effective amount of an siRNA or an AAV particle encoding an siRNA described herein.
  • a method of treating a subject having or diagnosed with having a disorder associated with tau expression e.g., aberrant tau expression.
  • the method comprising administering an effective amount of an siRNA or an AAV particle encoding an siRNA described herein.
  • the present disclosure provides, a method of treating a subject having or diagnosed with a tauopathy. The method comprising administering an effective amount of an siRNA or an AAV particle encoding an siRNA described herein.
  • the genetic disorder, neurological disorder e g., neurodegenerative disorder
  • disorder associated with tau expression e.g., aberrant tau expression
  • tauopathy is Alzheimer’s disease.
  • a short interfering ribonucleic acid (siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) which comprises a sense strand sequence and an antisense strand sequence, wherein the antisense sequence is complementary to at least 15, 16, 17, 18. 19, 20, or 21 contiguous nucleotides comprising 0, 1, 2, or 3 mismatches of a MAPT sequence comprising the nucleotide sequence of SEQ ID NO: 5024 or a nucleotide sequence provided in Table 3 or 19.
  • siRNA of embodiment 1 or 2 wherein the antisense strand is complementary 7 to at least 15, 16, 17, or 18, contiguous nucleotides with 0, 1, 2, or 3 mismatches to nucleotides 1300-1317, 1305-1322, 1860- 1877, 2279-2297, 2286-2303, 2402-2419, 2581-2958, 2584-2601, 2633-2650, or 2634-2653 of SEQ ID NO: 5024.
  • siRNA of any one of embodiments 1-3, wherein the sense strand comprises:
  • the antisense strand sequence comprises at least 15, 16, 17. 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one ofthe antisense strand sequences provided in Tables 3 4, 5, 9A, or 9B; and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one ofthe sense strand sequences provided in Tables 3 4, 5, 9A, or 9B, wherein the sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.
  • siRNA of embodiment 7. wherein the region of complementarity is 15-30, 19-21, or 25-30 nucleotides in length, e.g.. 17. 18, 20, 21, 22, 25, or 30 nucleotides in length.
  • tire antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4700 and tire sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4502-4505;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1. or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938. 4958. 4978, or 4998;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4697 and tire sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4495-4499;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4690 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4480-4484;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4694 and tire sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4492;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4691 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4485-4489;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014; (x) the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4701 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4506-4510;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4687 and the sense strand sequence comprises at least 15. 16, 17, 18, or 19 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4477;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4712 and tire sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2. 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4521;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4696 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4494; or
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4718 and the sense strand sequence comprises at least 15. 16, 17, 18, or 19 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4527.
  • tire antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4700 and the sense strand sequence comprises at least 15. 16, 17, 18. or 19 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4502- 4505;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 15, 16. 17. 18. 19. 20, or 21 contiguous nucleotides differing from the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938, 4958, 4978, or 4998:
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4697 and the sense strand sequence comprises at least 15, 16, 17, 18. or 19 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4495- 4499;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4690 and the sense strand sequence comprises at least 15. 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4480- 4484;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 15, 16. 17, 18, 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4922. 4942. 4962, 4982, 5002, or 5022:
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4694 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4492;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4691 and the sense strand sequence comprises at least 15. 16, 17, 18. or 19 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4485- 4489;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934. 4954, 4974, 4994, or 5014:
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4701 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4506- 4510; (xi) the antisense strand sequence comprises at least 15. 16.
  • the antisense strand sequence comprises at least 15, 16, 17. 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4687 and the sense strand sequence comprises at least 15. 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4477;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4712 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4521;
  • tire antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4696 and the sense strand sequence comprises at least 15. 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4494; or
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4718 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4527.
  • a short interfering ribonucleic acid (siRNA) for inhibiting expression of microtubule-associated protein tau (MAPT) which comprises a sense strand sequence and an antisense strand sequence, wherein:
  • the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of any one of SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912, 5080, 5104, or 5128; and
  • the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of any one of SEQ ID NOs: 4906, 4926. 4946, 4966, 4986, 5006, 4918, 4938, 4958. 4978, 4998, 4922, 4942, 4962, 4982, 5002, 5022. 5054. 5060, 5064, 5066, 5070, 5074, 4914. 4934. 4954, 4974, 4994, 5014, 4910, 4930.
  • sense strand sequence and the antisense strand sequence comprise a region of complementarity of at least 15 nucleotides.
  • An adeno-associated virus (AAV) viral genome comprising a nucleotide sequence positioned between two inverted terminal repeats (ITRs), wherein the nucleotide sequence encodes an siRNA for inhibiting MAPT, wherein the siRNA comprises a sense strand sequence and an antisense strand sequence, wherein:
  • tire antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides of any one of SEQ ID NOs: 4908, 4920, 4924, 5057, 4916, 4912. 5080, 5104, or 5128; and (ii) the sense strand sequence comprises at least 19.
  • siRNA of any one of embodiments 1-10 or the AAV viral genome of any one of embodiments 12-14 wherein the sense strand sequence comprises at least 19, 20. or 21 contiguous nucleotides of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, 5006. 4918. 4938, 4958, 4978, 4998, 4922, 4942. 4962. 4982, 5002, 5022, 4910, 4930, 4950, 4970, 4990, or 5010.
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938. 4958, 4978, or 4998;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022; (iv) the antisense strand sequence comprises at least 19. 20.
  • 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5101, 5108, 5112, 5116, 5120, or 5122;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5125, 5132, 5136, 5140, 5144, or 5146;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5077, 5084, 5088, 5092, 5096, or 5098; or
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5054, 5060, 5064, 5066, 5070, or 5074.
  • siRNA of any one of embodiments 1-10 or the AAV viral genome of any one of embodiments 12-16 wherein the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4906.
  • siRNA of any one of embodiments 1-10 or the AAV viral genome of any one of embodiments 12-16 wherein the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4918. 19.
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4922.
  • siRNA of any one of embodiments 1-10 or the AAV viral genome of any one of embodiments 12-16 wherein the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4966.
  • siRNA of any one of embodiments 1-10 or the AAV viral genome of any one of embodiments 12-16 wherein the antisense strand sequence comprises at least 19. 20. or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4970.
  • siRNA of any one of embodiments 1-10 or the AAV viral genome of any one of embodiments 12-16 wherein the antisense strand sequence comprises at least 19. 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4978.
  • siRNA of any one of embodiments 1-10 or the AAV viral genome of any one of embodiments 12-16 wherein the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4982.
  • tire antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4910;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4914;
  • the antisense strand sequence comprises at least 19. 20. or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5054;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4926;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4930;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4934;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4938;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and tire sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4942;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5060;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4946;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4950;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and tire sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4954;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4958;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4962;
  • tire antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5064;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4974;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5066;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4986;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and tire sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4990;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4994;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and tire sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4998;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5002;
  • the antisense strand sequence comprises at least 19, 20. or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and tire sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5070;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5006;
  • the antisense strand sequence comprises at least 19. 20. or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5010;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and tire sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5014;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4958;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5022;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5074;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and tire sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5077;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5084;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and tire sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5088;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5092;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5096;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5098;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5101;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5108;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5112;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5116;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5120;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5122;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5125;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and tire sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5132;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5136;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and tire sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5140;
  • the antisense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5144; or (xlvi) the antisense strand sequence comprises at least 19. 20. or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 19, 20, or 21 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5146.
  • tire antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4906. 4926. 4946, 4966, 4986, or 5006;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938, 4958, 4978, or 4998;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4922. 4942. 4962, 4982, 5002, or 5022;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4914. 4934. 4954, 4974, 4994, or 5014;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5101, 5108, 5112, 5116, 5120, or 5122;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5125, 5132, 5136, 5140, 5144, or 5146;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5077. 5084. 5088, 5092, 5096, or 5098; or
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5054, 5060, 5064, 5066, 5070, or 5074.
  • siRNA of any one of embodiments 1-11, 13, or 25-27 or the AAV viral genome of any one of embodiments 11-17 or 25-27 wherein the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4906.
  • siRNA of any one of embodiments 1-11, 13, or 25-27 or the AAV viral genome of any one of embodiments 11-16, 19, or 25-27 wherein the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 4922.
  • siRNA of any one of embodiments 1-11, 13, or 25-27 or the AAV viral genome of any one of embodiments 11-16, 20, or 25-27 wherein the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 4966.
  • siRNA of any one of embodiments 1-11, 13, or 25-27 or the AAV viral genome of any one of embodiments 1 1-16, 22, or 25-27 wherein the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4978.
  • siRNA of any one of embodiments 1-11, 13, or 25-27 or tire AAV viral genome of any one of embodiments 11-16, 23, or 25-27 wherein the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4982.
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4910;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4914;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5054;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4926;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4930;
  • tire antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4934;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4938; (viii) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924: and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4942;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and tire sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5060;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4946;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4950:
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4954;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4958;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4962;
  • tire antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5064;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4974;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5066;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4986;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912: and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4990;
  • tire antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and tire sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4994;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4998;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5002:
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5070;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5006;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5010;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5014;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4958;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5022;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5074;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080: and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5077;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5084;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5088;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5092:
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5096;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5098;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5101;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5108;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5112;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5116;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5120; (xl) the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5104: and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5122;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and tire sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5125;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5132;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5136:
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5140;
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from tire nucleotide sequence of SEQ ID NO: 5144; or
  • the antisense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises at least 20 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 5146.
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938. 4958, 4978, or 4998;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930. 4950, 4970, 4990, or 5010;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and tire sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5101, 5108. 5112, 5116, 5120, or 5122;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5125, 5132, 5136, 5140, 5144, or 5146;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5077, 5084. 5088, 5092, 5096, or 5098; or
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 5054, 5060, 5064, 5066, 5070, or 5074.
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4918.
  • tire antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4910;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4914;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5054;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4926;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4930;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4934;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4938;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4942;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5060;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4946;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4950;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4954;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4958;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4962;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5064;
  • tire antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4974;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5066;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4986;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4990;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4994;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4998;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5002;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5070;
  • the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 4908: and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5006;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5010;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5014;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4958;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5022;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5074;
  • the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5080: and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5077;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5084;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5088;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5092;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5096;
  • the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5098; (xxxv) the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5101 ;
  • the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5108;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104: and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5112;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5116;
  • the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5120;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5122;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5125;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5132;
  • the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5136;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5140;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5144; or
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5128; and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5146.
  • tire antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4700 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4502-4505;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938, 4958, 4978, or 4998;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4697 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4495-4499;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006;
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides from the nucleotide sequence of SEQ ID NO: 4690 and the sense strand sequence comprises at least 15, 16, 17, 18. or 19 contiguous nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4480- 4484;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4694 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4492;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4691 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4485-4489;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4701 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4506-4510;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4687 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4477;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4712 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4521;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4696 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4494; or
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4718 and the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4527.
  • siRNA of any one of embodiments 1-11 or 13-47 or the AAV viral genome of any one of embodiments 12-47 wherein (i) the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4420 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4905 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4421 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4909 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4422 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4913 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4423 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4917 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4424 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4921 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4410 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4925 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4411 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4929 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4412 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436;
  • the nucleotide sequence encoding the sense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 4933 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4413 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4937 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4419;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4414 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4941 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4415 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4945 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4416 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4949 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4417 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436;
  • tire nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4953 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4418 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437;
  • nucleotide sequence encoding tire sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4957 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4419 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4961 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4420 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4965 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4421 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4969 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4422 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4973 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4423 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4977 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4424 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4981 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4425 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4985 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4426 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435;
  • the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4989 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911;
  • the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4427 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4993 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4428 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4437;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4997 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4429 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5001 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4430 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4434;
  • the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5005 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907;
  • the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4431 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4435;
  • the nucleotide sequence encoding the sense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5009 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911;
  • the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4432 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4436;
  • the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5013 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4915;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4433 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4438;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5021 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5053 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5059 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5063 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056;
  • the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5065 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056;
  • the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5069 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5073 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5056;
  • the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5076 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079;
  • the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5083 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079;
  • the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5087 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5091 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5095 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5097 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5079;
  • the nucleotide sequence encoding the sense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5100 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5107 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5111 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5115 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5119 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103;
  • tire nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5121 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5103;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5124 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5131 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127;
  • tire nucleotide sequence encoding the sense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 5135 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127;
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5139 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127;
  • tire nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5143 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127; or
  • nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 5145 and the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 5127.
  • tire sense strand and the antisense strand comprise one mismatch
  • a modulatory polynucleotide comprising the siRNA of any one of embodiments 1-12 or 13-58.
  • modulatory polynucleotide of embodiment 61 or the AAV viral genome of embodiment 61, wherein:
  • the 5’ flanking region comprises the nucleotide sequence of any one of SEQ ID NOs: 4878- 4886; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4878-4886; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4878-4886;
  • the loop region comprises the nucleotide sequence of any of SEQ ID NOs: 4887-4896; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical thereto; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4887-4896; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4887-4896; and/or
  • the 3’ flanking region comprises the nucleotide sequence of any one of SEQ ID NOs: 4897- 4904; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4897-4904; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4897-4904.
  • tire nucleotide sequence encoding the 5’ flanking region comprises the nucleotide sequence of any of SEQ ID NOs: 4353-4361, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical thereto; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4353-4361; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4353-4361;
  • the nucleotide sequence encoding the loop region comprises the nucleotide sequence of any of SEQ ID NOs: 4362-4371; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical thereto; a nucleotide sequence comprising one, two. three, or four, but no more than five different nucleotides relative to the nucleotide sequence of any of SEQ ID NOs: 4362-4371; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4362-4371; and/or
  • the nucleotide sequence encoding the 3’ flanking region comprises the nucleotide sequence of any of SEQ ID NOs: 4372-4379; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical thereto; a nucleotide sequence comprising one, two.
  • nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of any of SEQ ID NOs: 4372-4379.
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879.
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4887.
  • a 3’ flanking region of SEQ ID NO: 4898 a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one. two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898.
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879.
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4888.
  • a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888; and
  • a 3’ flanking region of SEQ ID NO: 4898 a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to tire nucleotide sequence of SEQ ID NO: 4898.
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%. 80%. 85%. 90%. 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4887, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4887, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4887; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4887; and
  • a 3’ flanking region of SEQ ID NO: 4899 a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4899, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4899, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4899.
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880, a nucleotide sequence at least 70%, 75%. 80%. 85%. 90%. 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to tire nucleotide sequence of SEQ ID NO: 4880;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4891, a nucleotide sequence at least 70%. 75%. 80%. 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4891; and
  • a 3' flanking region of SEQ ID NO: 4900 a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900, a nucleotide sequence comprising one. two, three, four, five. six. or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4900, or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900.
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 70%, 75%. 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to tire nucleotide sequence of SEQ ID NO: 4880;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 70%. 75%. 80%. 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4891;
  • a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 70%, 75%. 80%. 85%. 90%. 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900.
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4355;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 70%. 75%. 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366;
  • a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 70%, 75%. 80%. 85%. 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375.
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4880;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4891; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4891; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4891; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to tire nucleotide sequence of SEQ ID NO: 4891;
  • a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900.
  • tire nucleotide sequence encoding the modulatory polynucleotide comprises:
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4355;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366;
  • a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one. two, three, four, five. six. or seven, but no more than ten modifications relative to SEQ ID NO: 4375.
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4880; a nucleotide sequence at least 70%, 75%. 80%. 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4880; a nucleotide sequence comprising one, two. three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4880; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to tire nucleotide sequence of SEQ ID NO: 4880;
  • a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4900; a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4900; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4900; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4900.
  • modulatory polynucleotide of any one of embodiments 59, 61-63, 67, 68, or 73 or the AAV viral genome of any one of embodiments 60-63, 67, 68, or 73, where the nucleotide sequence encoding the modulatory polynucleotide comprises:
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4355; a nucleotide sequence at least 70%, 75%. 80%. 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4355; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4355; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to tire nucleotide sequence of SEQ ID NO: 4355;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4366; a nucleotide sequence at least 70%. 75%. 80%. 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4366; a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4366; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4366;
  • a 3’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4375; a nucleotide sequence at least 70%, 75%. 80%. 85%. 90%. 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4375; a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4375; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to SEQ ID NO: 4375. 75.
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 70%, 75%. 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908;
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one. two, three, four, five. six. or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 70%, 75%. 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two. three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907;
  • a 3‘ flanking region of SEQ ID NO: 4373 (v) a 3‘ flanking region of SEQ ID NO: 4373. a nucleotide sequence at least 70%. 75%. 80%. 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373.
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one. two, three, four, five. six. or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912;
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 70%, 75%. 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to tire nucleotide sequence of SEQ ID NO: 4354;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 70%, 75%. 80%. 85%. 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4911;
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one. two, three, four, five. six. or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 70%, 75%. 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two. three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920;
  • a 3‘ flanking region of SEQ ID NO: 4898 a nucleotide sequence at least 70%. 75%. 80%. 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4898, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4898.
  • modulatory polynucleotide of any one of embodiments 59, 61-63. 65. 68, or 79 or the AAV viral genome of any one of embodiments 60-63, 65, 68, or 79, wherein the nucleotide sequence encoding the modulatory polynucleotide comprises:
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 70%, 75%. 80%. 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919;
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4879, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4879, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4879; or a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4879;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4888, a nucleotide sequence at least 70%, 75%. 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4888, a nucleotide sequence comprising one, two, three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4888; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4888;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924;
  • a 5’ flanking region comprising the nucleotide sequence of SEQ ID NO: 4354, a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4354, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4354; or a nucleotide sequence comprising one. two, three, four, five. six. or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4354;
  • a loop region comprising the nucleotide sequence of SEQ ID NO: 4363, a nucleotide sequence at least 70%, 75%. 80%, 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4363, a nucleotide sequence comprising one, two. three, or four, but no more than five different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4363; or a nucleotide sequence comprising one, two, three, or four, but no more than five modifications relative to the nucleotide sequence of SEQ ID NO: 4363;
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923;
  • a 3‘ flanking region of SEQ ID NO: 4373 (v) a 3‘ flanking region of SEQ ID NO: 4373. a nucleotide sequence at least 70%. 75%. 80%. 85%, 90%, 95% 96%, 97%, 98%, 99% identical to SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of SEQ ID NO: 4373, a nucleotide sequence comprising one, two, three, four, five, six, or seven, but no more than ten modifications relative to the nucleotide sequence of SEQ ID NO: 4373.
  • the modulatory polynucleotide of any one of embodiments 59 or 61-82 or the AAV viral genome of any one of embodiments 62-82, wherein the nucleotide sequence encoding the modulatory’ polynucleotide comprises the nucleotide sequence of the nucleotide sequence of any one of SEQ ID NOs: 4380-4409 or 5027-5050, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • nucleotide sequence encoding the modulatory polynucleotide comprises the nucleotide sequence of SEQ ID NO: 4390, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • An adeno-associated virus (AAV) viral genome comprising a promoter operably linked to a nucleic acid encoding the modulatory polynucleotide of any one of embodiments 59-90 or the siRNA of any one of embodiments 1-11 or 13-58.
  • AAV adeno-associated virus
  • tire AAV viral genome further comprises a promoter operably linked to the nucleotide sequence encoding the sense strand sequence and the antisense strand sequence or the modulatory polynucleotide.
  • the promoter comprises the nucleotide sequence of any one of the nucleotide sequences provided in Table 2; a nucleotide sequence comprising at least one, two. three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to any one of the nucleotide sequences provided in Table 2; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of the nucleotide sequences provided in Table 2.
  • the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5199.
  • the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476.
  • ITR inverted terminal repeat
  • tire ITR comprises the nucleotide sequence of SEQ ID NO: 5197, 5200, 4469, or 4470; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197, 5200, 4469, or 4470; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 5197, 5200, 4469, or 4470.
  • the AAV viral genome of embodiment 103, wherein the ITR positioned 5’ relative to the nucleic acid encoding the modulator polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5197 or 4469; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197 or 4469; or a nucleotide sequence with at least 80%, 85%, 90%. 92%. 95%. 96%. 97%, 98%, or 99% sequence identity to SEQ ID NO: 5197 or 4469.
  • the AAV viral genome of embodiment 103, wherein the ITR positioned 3’ relative to the nucleic acid encoding the modulator polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5200 or 4470; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200 or 4470; or a nucleotide sequence with at least 80%, 85%, 90%. 92%. 95%. 96%. 97%. 98%. or 99% sequence identity to SEQ ID NO: 5200 or 4470.
  • the ITR positioned 5 ’ relative to the nucleic acid encoding the modulatory’ polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92% 95%. 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; and
  • the ITR positioned 3’ relative to the nucleic acid encoding the modulatory’ polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92% 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g.. substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.
  • the ITR positioned 5 ’ relative to the nucleic acid encoding tire modulatory polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 4469; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%. 98%. or 99% identical to SEQ ID NO: 4469; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4469; and
  • the ITR positioned 3’ relative to the nucleic acid encoding the modulatory’ polynucleotide or siRNA comprises the nucleotide sequence of SEQ ID NO: 4470; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%. 98%. or 99% identical to SEQ ID NO: 4470; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g.. substitutions, insertions, or deletions, relative to SEQ ID NO: 4470.
  • the enhancer comprises:
  • nucleotide sequence of SEQ ID NO: 4471 or 4472 (ii) the nucleotide sequence of SEQ ID NO: 4471 or 4472; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, c.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471 or 4472; or a nucleotide sequence with at least 80%, 85%, 90%. 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4471 or 4472.
  • the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, c.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4471.
  • the enhancer and promoter comprise the nucleotide sequence of SEQ ID NO: 4473 or 4474; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4473 or 4474; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4473 or 4474.
  • hBG intron human beta globin intron
  • nucleotide sequence of SEQ ID NO: 4475 (ii) the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence with at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4475.
  • AAV viral genome of any one of embodiments 12-58 or 60-115 wherein the AAV viral genome further comprises a nucleotide sequence encoding a miR binding site, e.g., a miR binding site that modulates, e.g., reduces expression of the payload encoded by the viral genome in a cell or tissue where the corresponding miRNA is expressed.
  • a miR binding site e.g., a miR binding site that modulates, e.g., reduces expression of the payload encoded by the viral genome in a cell or tissue where the corresponding miRNA is expressed.
  • the encoded miR binding site modulates, e.g., reduces expression of the encoded payload in a cell or tissue of the DRG, liver, heart, hematopoietic lineage, or a combination thereof.
  • AAV viral genome of any one of embodiments 12-58 or 60-117, wherein the AAV viral genome comprises at least 1-5 copies of the encoded miR binding site, e g., at least 1, 2, 3. 4, or 5 copies, optionally wherein the at least 1-5 copies are continuous (e.g., not separated by a spacer) or the at least 1-5 copies are separated by a spacer.
  • a Rep protein e.g., a non-structural protein
  • Rep protein comprises a Rep78 protein, a Rep68, Rep52 protein, and/or a Rep40 protein (e.g.. a Rep78 and a Rep52 protein).
  • an enhancer e.g., a CMVie enhancer or variant thereof
  • a promoter e.g., a CBA promoter or variant thereof
  • an intron e.g., an hBG intron or variant thereof
  • a nucleic acid sequence encoding a modulatory polynucleotide (e.g. the modulatory polynucleotide of any one of embodiments 59-90);
  • tire enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;
  • a promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%. 90%. 92%. 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;
  • tire intro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;
  • nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises any one of SEQ ID NOs: 4380-4409 or 5027-5050. or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto;
  • polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and
  • an ITR wherein the ITR comprises tire nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;
  • an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%. 90%. 92%. 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;
  • a promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;
  • the intro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g.. substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;
  • nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises any one of SEQ ID NOs: 4405, 4408, 4409, 4390, 4391, 4393, or 4394, or nucleotide sequence at least 80%. 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto;
  • polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and
  • an ITR wherein the ITR comprises tire nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%. 90%. 92%. 95%. 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197; (ii) an enhancer, wherein the enhancer comprises the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%
  • a promoter comprising the nucleotide sequence of SEQ ID NO: 5199: a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;
  • the intro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%. 96%. 97%. 98%. or 99% identical to SEQ ID NO: 4475;
  • nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4405, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto;
  • polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%. 90%. 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;
  • an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471 ;
  • a promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%. 90%. 92%. 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;
  • tire intro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;
  • nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4408, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%. 97%. 98%. or 99% identical thereto;
  • polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and
  • an ITR wherein the ITR comprises tire nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;
  • an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471; (iii) a promoter, wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%
  • the intro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g.. substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;
  • nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4409, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto;
  • polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and
  • an ITR wherein the ITR comprises tire nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%. 90%. 92%. 95%. 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;
  • an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;
  • a promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;
  • the intro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%. 96%. 97%. 98%, or 99% identical to SEQ ID NO: 4475;
  • nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4390, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto;
  • polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%. 90%. 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;
  • an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%. 90%. 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;
  • a promoter comprising the nucleotide sequence of SEQ ID NO: 5199: a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199; (iv) an intron, wherein the intro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%,
  • nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4391, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%. 97%. 98%. or 99% identical thereto;
  • polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and
  • an ITR wherein the ITR comprises tire nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;
  • an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;
  • a promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;
  • the intro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;
  • nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4393, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto;
  • polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%. 90%. 92%. 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5197; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5197; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5197;
  • an enhancer comprising the nucleotide sequence of SEQ ID NO: 4471; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4471; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4471;
  • a promoter comprising the nucleotide sequence of SEQ ID NO: 5199; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%. 90%. 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;
  • tire intro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475; (v) a nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises SEQ ID NO: 4394, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto;
  • polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 5200; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5200; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5200.
  • an ITR wherein the ITR comprises the nucleotide sequence of SEQ ID NO: 4469; a nucleotide sequence at least 80%, 85%. 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4469; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4469;
  • an enhancer comprising the nucleotide sequence of SEQ ID NO: 4472; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4472; or a nucleotide sequence at least 80%, 85%. 90%. 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4472;
  • a promoter comprising the nucleotide sequence of SEQ ID NO: 5199: a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 5199; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5199;
  • the intro comprises the nucleotide sequence of SEQ ID NO: 4475; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4475; or a nucleotide sequence at least 80%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4475;
  • nucleotide sequence encoding a modulatory polynucleotide, wherein the nucleotide sequence comprises any one of SEQ ID NOs: 4380-4409 or 5027-5050, or nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%.
  • polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 4476; a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4476; or a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4476; and
  • an ITR wherein the ITR comprises tire nucleotide sequence of SEQ ID NO: 4470; a nucleotide sequence at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 4470; or a nucleotide sequence comprising at least one, two, three, four, five, six, or seven but no more than ten modifications, e.g., substitutions, insertions, or deletions, relative to SEQ ID NO: 4470.
  • AAV viral genome of any one of embodiments 12-58, 60-96, 98-108, or 110-133 which comprises the nucleotide sequence of any one of SEQ ID NOs: 5149-5196, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%. 96%. 97%. 98%. or 99% identical to any one of SEQ ID NOs: 5149-5196.
  • the AAV viral genome of any one of embodiments 12-58, 60-96, 98-108, 110-133, or 134 which comprises the nucleotide sequence of any one of SEQ ID NOs: 5173, 5195, 5196, 5182, 5183, 5184, or 5185, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 5173, 5195, 5196, 5182, 5183. 5184, or 5185.
  • AAV viral genome of any one of embodiments 12-58, 60-96, 98-108, 110-124, 126, or 133-135. which comprises the nucleotide sequence of SEQ ID NO: 5195. or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5195.
  • SEQ ID NO: 5196 which comprises the nucleotide sequence of SEQ ID NO: 5196, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 5196.
  • An AAV particle comprising the AAV viral genome of any one of embodiments 12-58 or 60-143, an AAV viral genome encoding the modulatory polynucleotide of any one of embodiments 59-90, or an AAV viral genome encoding the siRNA of any one of embodiments 11 or 13-58, and an AAV capsid protein.
  • the AAV particle of embodiment 48 wherein the AAV capsid protein comprises an AAV5 capsid protein, an AAV9 capsid protein, VOY 101 capsid protein, a PHPeB capsid protein, a PHP.B capsid protein, a PHP.N capsid protein, an AAV1 capsid protein, a VOY9P39 capsid protein, an AAV2 capsid protein, an AAVrhlO capsid protein, or a variant thereof (e.g., an AAV9 capsid protein or a variant thereof or an AAV5 capsid protein or variant thereof).
  • the AAV capsid protein comprises an AAV9 capsid or variant thereof.
  • AAV particle of embodiment 144 or 145, wherein the AAV capsid protein comprises an AAV5 capsid or variant thereof.
  • the AAV capsid protein comprises an amino acid sequence provided in Table 1 or an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identical thereto; or
  • the nucleotide sequence encoding the AAV capsid protein comprises any one of tire nucleotide sequences in Table 1, or a nucleotide sequence at least 70%. 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% identical thereto.
  • a vector comprising the AAV viral genome of any one of embodiments 12-58 or 60-143, a nucleotide sequence encoding the modulatory polynucleotide of any one of embodiments 59-90, or a nucleotide sequence encoding the siRNA of any one of embodiments 11 or 13-58.
  • a cell comprising the AAV particle of any one of embodiments 144-148, the AAV viral genome of any one of embodiments 12-58 or 60-143, the modulatory polynucleotide of any one of embodiments 59-90, or the siRNA of any one of embodiments 11 or 13-58.
  • the cell of embodiment 150 wherein the cell is a mammalian cell or an insect cell.
  • the cell of embodiment 150 or 151, wherein the cell is a cell of a brain region or a spinal cord region (e.g., a CNS cell).
  • a method of making an AAV particle comprising: (i) providing a host cell comprising the AAV viral genome of any one of embodiments 12-58 or 60- 143, an AAV viral genome encoding the modulatory polynucleotide of any one of embodiments 59-90, or a viral genome encoding the siRNA of any one of embodiments 11 or 13-58;
  • a pharmaceutical composition comprising the AAV particle of any one of embodiments 144-148, an AAV particle comprising the AAV viral genome of any one of embodiments 12-58 or 60-143, the modulatory polynucleotide of any one of embodiments 59-90, orthe siRNA of any one of embodiments 11 or 13-58, and a pharmaceutically acceptable excipient.
  • a method of delivering an siRNA for inhibiting MAPT expression e.g., MAPT gene, mRNA, or protein expression
  • a method of delivering an siRNA for inhibiting MAPT expression comprising administering an effective amount of the pharmaceutical composition of embodiment 159, the AAV particle of any one of embodiments 144-159, an AAV particle comprising the AAV viral genome of any one of embodiments 12-58 or 60-143, the modulatory polynucleotide of any one of embodiments 59-90, or the siRNA of any one of embodiments 11 or 13-58, thereby delivering the siRNA for inhibiting MAPT expression to the cell.
  • an siRNA for inhibiting MAPT expression e.g., MAPT gene, mRNA, or protein expression
  • Tire method of embodiment 160 wherein the cell is a cell of a brain region or a spinal cord region.
  • embodiment 160 or 162 The method of embodiment 160 or 161, wherein the cell is a cell of the cortex, hippocampus, thalamus, or brainstem. 163. The method of any one of embodiments 160-162, wherein the cell is a neuron, an astrocyte, a glial cell, or an oligodendrocyte.
  • a reference level e.g., the mRNA levels in a cell that has not been delivered or prior to delivering the AAV particle, modulatory polynucleotide, siRNA, or pharmaceutical composition
  • an assay e.g., an assay as described in Example 6
  • a cell of a brain region e.g., cortex, hippocampus, thalamus, or brain stem
  • a reference level e.g., the protein levels in a cells that has not been delivered or prior to delivering the AAV particle, modulatory polynucleotide, siRNA, or pharmaceutical composition
  • an assay e.g., an assay as described in Example 6
  • Tire method of embodiment 166 or 167, wherein the subject has or has been diagnosed with having a neurological disorder e.g., a neurodegenerative disorder.
  • a method of treating a subject having or diagnosed with having a genetic disorder comprising administering to the subject an effective amount of tire pharmaceutical composition of embodiment 159, the AAV particle of any one of embodiments 144-159, an AAV particle comprising the AAV viral genome of any one of embodiments 12-58 or 60-143, the modulatory’ polynucleotide of any one of embodiments 59-90, or the siRNA of any one of embodiments 1 1 or 13-58, thereby treating the subject having or diagnosed with having the genetic disorder, e.g., the monogenic disorder or the polygenic disorder.
  • a genetic disorder e.g., a monogenic disorder or a polygenic disorder
  • a method of treating a subject having or diagnosed with having a neurological disorder comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 159, the AAV particle of any one of embodiments 144-159, an AAV particle comprising the AAV viral genome of any one of embodiments 12-58 or 60-143, the modulatory’ polynucleotide of any one of embodiments 59-90, or the siRNA of any’ one of embodiments 11 or 13-58, thereby treating the subject having or diagnosed with having the neurological disorder (e.g., the neurodegenerative disorder).
  • a neurological disorder e.g. a neurodegenerative disorder
  • a method of treating a subject having or diagnosed with having a disorder associated with tau expression, e.g., aberrant tau expression comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 159, the AAV particle of any one of embodiments 144-159, an AAV particle comprising the AAV viral genome of any one of embodiments 12-58 or 60-143, the modulatory polynucleotide of any one of embodiments 59-90. or the siRNA of any one of embodiments 11 or 13-58, thereby treating the subject having or diagnosed with having the disorder associate with tau expression, e.g., aberrant tau expression.
  • a method of treating a subject having or diagnosed with having a tauopathy comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 159, the AAV particle of any one of embodiments 144-159. an AAV particle comprising the AAV viral genome of any one of embodiments 12-58 or 60-143, the modulatory polynucleotide of any one of embodiments 59-90, or the siRNA of any one of embodiments 11 or 13-58, thereby’ treating the subject having or diagnosed with having the tauopathy.
  • the genetic disorder, neurological disorder e.g., neurodegenerative disorder
  • disorder associated with tau expression e.g.. aberrant tau expression
  • tauopathy is Alzheimer’s disease (AD), Frontotemporal dementia (FTD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), Dravet syndrome (DS), neurodegenerative disease, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), Down’s syndrome, Pick’s disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS). Prion diseases.
  • CJD Multiple system atrophy, mild cognitive impairment, Tangle-only dementia, or Progressive subcortical gliosis.
  • treating comprises prevention of progression of the genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g.. aberrant tau expression), and/or tauopathy in the subject.
  • neurological disorder e.g., neurodegenerative disorder
  • disorder associated with tau expression e.g.. aberrant tau expression
  • any one of embodiments 171-176 further comprising performing a blood test, an imaging test (e.g., a PET scan or a PET scan in combination with biomarker, e.g., serum biomarker staining), a CNS biopsy sample, or an aqueous cerebral spinal fluid biopsy, optionally wherein the blood test, imaging test, biopsy sample, or aqueous cerebral spinal fluid biopsy is performed prior to, during, or after treatment with the AAV particle, modulatory polynucleotide. siRNA, or phannaceutical composition.
  • a biomarker of tau pathology e.g., 18 F-flortaucipir, plasma ptau 181, or 1S F- PM-PBB3
  • a reference e.g., a subject that as not received the AAV particle
  • an assay e.g., an assay as described in Example 6
  • a cell of a brain region e.g., cortex, hippocampus, thalamus, or brain stem
  • a reference level e.g., the protein levels in a subject that has not received or prior to receiving the AAV particle, modulatory polynucleotide, siRNA, or pharmaceutical composition
  • an assay e.g., an assay as described in Example 6
  • ICM intra-cistema magna
  • an AAV particle comprising the AAV viral genome of any one of embodiments 12-58 or 60-143, the modulatory polynucleotide of any one of embodiments 59-90. or the siRNA of any one of embodiments 11 or 13-58, for use in the manufacture of a medicament.
  • a genetic disorder e.g., neurodegenerative disorder
  • disorder associated with tan expression e.g., aberrant tau expression
  • tauopathy e.g., aberrant tau expression
  • embodiment 159 Use of the pharmaceutical composition of embodiment 159, the AAV particle of any one of embodiments 144-159, an AAV particle comprising the AAV viral genome of any one of embodiments 12-58 or 60-143. the modulatory polynucleotide of any one of embodiments 59-90, or the siRNA of any one of embodiments 11 or 13-58, in the manufacture of a medicament for delivering an siRNA for inhibiting MAPT expression to a cell.
  • embodiment 159 Use of the pharmaceutical composition of embodiment 159, the AAV particle of any one of embodiments 144-159, an AAV particle comprising the AAV viral genome of any one of embodiments 12-58 or 60-143. the modulatory polynucleotide of any one of embodiments 59-90, or the siRNA of any one of embodiments 11 or 13-58, in the manufacture of a medicament.
  • composition of embodiment 159 Use of the pharmaceutical composition of embodiment 159, the AAV particle of any one of embodiments 144-159, an AAV particle comprising the AAV viral genome of any one of embodiments 12-58 or 60-143, the modulatory polynucleotide of any one of embodiments 59-90, or the siRNA of any one of embodiments 11 or 13-58. in the manufacture of a medicament for treating a genetic disorder, neurological disorder (e.g., neurodegenerative disorder), disorder associated with tau expression (e.g., aberrant tau expression), and/or tauopathy.
  • neurological disorder e.g., neurodegenerative disorder
  • tau expression e.g., aberrant tau expression
  • tauopathy e.g., aberrant tau expression
  • FIG. 1 is a graph depicting the relative R/F activity as % over non-target control (NTC) on the Y- axis post-transfection with the modulatory polynucleotide constructs targeting MAPT indicated on the X-axis (from left to right: VOYTaumiR-102-530 (SEQ ID NO: 4380), VOYTaumiR-102-556 (SEQ ID NO: 4381), VOYTaumiR- 102-579 (SEQ ID NO: 4383), VOYTaumiR- 102-586 (SEQ ID NO: 4384), VOYTaumiR- 104- 530 (SEQ ID NO: 4385), VOYTaumiR- 104-556 (SEQ ID NO: 4386). VOYTaumiR- 104-579 (SEQ ID NO: 4388). VOYTaumiR- 104-586 (SEQ ID NO: 4389), VOYTaumiR-109-
  • VOYTaumiR-109-556 (SEQ ID NO: 4391), VOYTaumiR- 109-579 (SEQ ID NO: 4393), VOYTaumiR- 109- 586 (SEQ ID NO: 4394), VOYTaumiR-114-530 (SEQ ID NO: 4395).
  • VOYTaumiR-114-556 (SEQ ID NO: 4396), VOYTaumiR-1 14-579 (SEQ ID NO: 4398), VOYTaumiR-1 14-586 (SEQ ID NO: 4399), VOYTaumiR-116-530 (SEQ ID NO: 4400), VOYTaumiR-116-556 (SEQ ID NO: 4401), VOYTaumiR-116- 579 (SEQ ID NO: 4403), VOYTaumiR-116-586 (SEQ ID NO: 4404), VOYTaumiR- 127-530 (SEQ ID NO: 4405), VOYTaumiR- 127-556 (SEQ ID NO: 4406), VOYTaumiR-127-579 (SEQ ID NO: 4408). and VOYTaumiR-127-586 (SEQ ID NO: 4409)).
  • FIG. 2 is a graph showing the fold-change in MAPT mRNA remaining for each vectorized modulatory polynucleotide relative to the non-target control (fold change relative to NTC) on the Y-axis post- transfection with the modulatory' polynucleotide constructs targeting MAPT indicated on the X-axis (from left to right: mock, non-target control (NTC), VOYTaumiR-127-530 (SEQ ID NO: 4405), VOYTaumiR- 127-556 (SEQ ID NO: 4406), VOYTaumiR-127-579 (SEQ ID NO: 4408), VOYTaumiR-127-586 (SEQ ID NO: 4409).
  • NTC non-target control
  • VOYTaumiR-127-530 SEQ ID NO: 4405
  • VOYTaumiR- 127-556 SEQ ID NO: 4406
  • VOYTaumiR-127-579 SEQ ID
  • VOYTaumiR- 116-530 (SEQ ID NO: 4400), VOYTaumiR- 116-556 (SEQ ID NO: 4401). VOYTaumiR-116-579 (SEQ ID NO: 4403), VOYTaumiR-116-586 (SEQ ID NO: 4404), VOYTaumiR-114- 530 (SEQ ID NO: 4395), VOYTaumiR-114-556 (SEQ ID NO: 4396), VOYTaumiR- 114-579 (SEQ ID NO: 4398), VOYTaumiR-114-586 (SEQ ID NO: 4399), VOYTaumiR-109-530 (SEQ ID NO: 4390), VOYTaumiR- 109-556 (SEQ ID NO: 4391), VOYTaumiR- 109-579 (SEQ ID NO: 4393), VOYTaumiR- 109- 586 (SEQ ID NO
  • VOYTaumiR-102-530 (SEQ ID NO: 4380), VOYTaumiR- 102-556 (SEQ ID NO: 4381), VOYTaumiR- 102- 579 (SEQ ID NO: 4383), and VOYTaumiR- 102-586 (SEQ ID NO: 4384)).
  • FIG. 3 is a graph showing the fold-change in MAPT mRNA remaining for each vectorized modulatory polynucleotide relative to the non-target control (fold change relative to NTC) on the Y -axis post- transfection with increasing concentrations (0.05 pg, 0.16 pg.
  • VOYTaumiR-127-530 SEQ ID NO: 4405
  • VOYTaumiR- 127-556 SEQ ID NO: 4406
  • VOYTaumiR-127-579 SEQ ID NO: 4408
  • VOYTaumiR-127-586 SEQ ID NO: 4409
  • VOYTaumiR-109-530 SEQ ID NO: 4390
  • VOYTaumiR- 109-556 SEQ ID NO: 4391
  • VOYTaumiR- 109-579 SEQ ID NO: 4393
  • VOYTaumiR- 109- 586 SEQ ID NO: 4394
  • VOYTaumiR-116-579 SEQ ID NO: 4403
  • FIG. 4 is a graph depicting the fold-change in MAPT mRNA remaining for each vectorized modulatory polynucleotide relative to the non-target control (fold change relative to NTC) on the Y-axis post- transfection with the indicated concentrations (0.5 pg or 1.0 pg) of the modulatory polynucleotides on the X- axis (from left to right: mock, GFP, NTC, MAPT antisense oligonucleotide (ASO) positive control, VOYTaumiR-127-530 (SEQ ID NO: 4405).
  • ASO MAPT antisense oligonucleotide
  • VOYTaumiR- 109-530 (SEQ ID NO: 4390), VOYTaumiR- 102- 582 (SEQ ID NO: 5027), VOYTaumiR- 104-582 (SEQ ID NO: 5031).
  • VOYTaumiR- 109-582 (SEQ ID NO: 5035), VOYTaumiR- 1 14-582 (SEQ ID NO: 5039), VOYTaumiR-127-582 (SEQ ID NO: 5047), VOYTaumiR-102-587 (SEQ ID NO: 5028), VOYTaumiR- 109-587 (SEQ ID NO: 5036), VOYTaumiR-114- 587 (SEQ ID NO: 5040), VOYTaumiR-104-552 (SEQ ID NO: 5033), VOYTaumiR- 104-549 (SEQ ID NO: 5034), and VOYTaumiR-116-549 (SEQ ID NO: 5046).
  • FIGs. 5A-5E are a series of graphs depicting the vector genome copies per diploid cells in the cortex (FIG. 5A), hippocampus (FIG. 5B), brainstem (FIG. 5C), thalamus (FIG. 5D), or liver (FIG. 5E) of mice following intravenous injection of the vehicle control or AAV particles comprising the VOY9P39 capsid encoding the VOYTaumiR- 127-530 modulatory polynucleotide (VOY9P39 127-530) at a dose of 3el2 vg/kg, le 13 vg/kg, or 3el3 vg/kg.
  • FIGs. 6A-6D are a series of graphs depicting the fold-change in MAPT mRNA levels remaining post-treatment in each treatment group relative to the vehicle on the Y-axis, in the cortex (FIG. 6A), hippocampus (FIG. 6B), thalamus (FIG. 6C), or brainstem (FIG.
  • mice following intravenous injection of AAV particles comprising the payload and capsid combinations indicated on the X-axis, which are from left to right: vehicle control, VOY9P39 capsid and mCherry reporter control at 3el3 vg/kg, VOY9P39 capsid and non-target control (NTC) at 3el3 vg/kg, VOY9P39 capsid and VOYTaumiR- 127-530 modulatory polynucleotide (127-530) at 3el2 vg/kg, VOY9P39 capsid and VOYTaumiR- 127-530 modulatory polynucleotide (127-530) at le 13 vg/kg, VOY9P39 capsid and VOYTaumiR- 127-530 modulatory polynucleotide (127-530) at 3el3 vg/kg, VOY101 capsid and mCherry
  • Statistical significance was evaluated with a one-way ANOVA with Tukey’s multiple comparison with p- value as shown on the graphs.
  • FIGs. 7A-7D are a series of graphs depicting the MAPT protein levels remaining post-treatment in each treatment group relative to the vehicle in the cortex (FIG. 7A), hippocampus (FIG. 7B), thalamus (FIG. 7C), or brainstem (FIG. 7D) of mice following intravenous injection of the vehicle control (vehicle): or AAV particles comprising the VOY9P39 capsid encoding VOYTaumiR-127-530 modulatory polynucleotide (127-530) administered at a dose of 3el2 vg/kg, le 13 vg/kg, or 3el3 vg/kg. The percentages above the bars represent the percent knockdown of tau protein following treatment. Statistical significance was evaluated with a one-way ANOVA with Tukey’s multiple comparison.
  • FIGs. 8A-8D are a series of graphs depicting tire MAPT mRNA levels remaining post-treatment in each treatment group relative to the vehicle in the cortex (FIG. 8A), hippocampus (FIG. 8B), thalamus (FIG. 8C), or brainstem (FIG.
  • mice following intravenous injection of the vehicle control (vehicle): AAV particles comprising the VOY9P39 capsid encoding the non-target control (NTC) at dose of lei 3 vg/kg (C9P39-NTC 1E13); AAV particles comprising the VOY9P39 capsid encoding the VOYTaumiR-127-530 modulatory polynucleotide at a dose of lcl2 vg/kg (C9P39-127.530 1E12) or 1c 13 vg/kg (C9P39- 127.530 1E13); or AAV particles comprising the VOY9P39 capsid encoding the VOYTaumiR-127-579 modulatory polynucleotide at a dose of le 13 vg/kg (C9P39-127.579 1E13).
  • Statistical significance was evaluated with a one-way ANOVA with Tukey’s multiple comparison with p-value as shown on the graphs
  • compositions comprising isolated, e.g., recombinant, viral particles, e.g., AAV particles, for delivery, e.g., vectorized delivery, of an RNA agent for targeting MAPT (e.g., a siRNA duplex for targeting MAPT) and methods of making and using the same.
  • an RNA agent for targeting MAPT e.g., a siRNA duplex for targeting MAPT
  • the RNA agent for targeting MAPT is siRNA duplex that modulates, e.g., inhibits MAPT expression, e g., a siRNA duplex for targeting MAPT as described herein.
  • the recombinant AAV particles will include a viral genome comprising a nucleotide sequence, e.g., encoding a transgene encoding an RNA agent for targeting MAPT (e.g., a siRNA duplex for targeting MAPT) and an AAV capsid protein, e.g., an AAV capsid variant described herein.
  • a viral genome comprising a nucleotide sequence, e.g., encoding a transgene encoding an RNA agent for targeting MAPT (e.g., a siRNA duplex for targeting MAPT) and an AAV capsid protein, e.g., an AAV capsid variant described herein.
  • Mutations in the MAPT gene were identified in the autosomal dominantly inherited tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), which demonstrates that mutations in the MAPT gene and/or tau protein could lead to neurodegenerative changes in the brain.
  • Mutant tau is considered more amyloidogenic than wild-type tau, meaning it is more likely to become hyperphosphorylated and to aggregate as NFT (Hutton, M. et al., 1998, Nature 393(6686): 702-5), and these NFT can be composed of pathological forms of tau including, but not limited to, hyperphosphorylated, misfolded and aggregated tau species, each of which has yielded a set of avidly pursued targets.
  • Hyperphosphorylation of tau depresses its binding to microtubules and microtubule assembly/stability activity. Further, hyperphosphorylation of tau renders it prone to misfolding and aggregation. Without wishing to be bound by theory, it is believed in some embodiments that administration of an siRNA targeting MAPT (e.g..
  • a mutated MAPT gene or a wild-type MAPT gene can reduce tau, e.g., pathological tau, protein expression, aggregation, hyperphosphorylation, and/or misfolding, thereby modulating, e.g., reducing or slowing, pathology associated with aberrant tau expression and/or tauopathies (e.g., Alzheimer’s disease (AD), frontotemporal dementia (FTD), and/or Dravet syndrome (DS)).
  • tauopathies e.g., Alzheimer’s disease (AD), frontotemporal dementia (FTD), and/or Dravet syndrome (DS)
  • an AAV particle or plurality of AAV particles for the vectorized delivery of an RNA agent for targeting MAPT e.g., a siRNA duplex for targeting MAPT
  • an RNA agent for targeting MAPT e.g., a siRNA duplex for targeting MAPT
  • CNS central nervous system
  • robust expression of the RNA agent targeting MAPT in the subject e.g., a subject having or diagnosed with having a disease associated with expression of tau or a neurological disorder described herein (e.g., atauopathy).
  • compositions for delivering a functional RNA agent for targeting MAPT by adeno-associated virus particles are provided.
  • AAVs adeno-associated virus particles
  • an AAV particle e.g., an AAV particle comprising a an AAV capsid polypeptide, as described herein, or plurality of particles
  • AAVs Adeno-associated viruses
  • AAV particles Adeno-associated viruses
  • compositions comprising isolated, e.g., recombinant, viral particles, e.g., AAV particles, for delivery, e.g., vectorized delivery, of a polynucleotide, e.g., a MAPT targeting siRNA, and methods of making and using the same.
  • viral particles e.g., AAV particles
  • a polynucleotide e.g., a MAPT targeting siRNA
  • an adeno-associated virus comprises a small non-enveloped icosahedral capsid virus of the Parvoviridae family and is characterized by a single stranded DNA viral genome.
  • the parvoviruses and other members of the Parvoviridae family are generally described in Kenneth I. Berns, “Parvoviridae: The Viruses and Their Replication," Chapter 69 in FIELDS VIROLOGY (3d Ed. 1996). the contents of which are incorporated by reference in their entirety.
  • AAV is capable of replication in vertebrate hosts including, but not limited to. human, primate, bovine, canine, equine, and ovine species
  • an AAV particle is used as a biological tool due to a relatively simple structure, their ability to infect a wide range of cells (including quiescent and dividing cells) without integration into the host genome and without replicating, and their relatively benign immunogenic profile.
  • the genome of the virus may be manipulated to contain a minimum of components for the assembly of a functional recombinant virus, or viral particle, which is loaded with or engineered to target a particular tissue and express or deliver a desired payload, e.g., a polynucleotide encoding a siRNA for targeting MAPT.
  • the AAV particle is a naturally occurring (e.g., wild-type) AAV or a recombinant AAV.
  • the wild-type AAV viral genome is a linear, single -stranded DNA (ssDNA) molecule approximately 5.000 nucleotides (nt) in length.
  • inverted terminal repeats ITRs
  • an AAV viral genome typically comprises two ITR sequences.
  • ITRs have a characteristic T-shaped hairpin structure defined by a self-complementary region (145nt in wild-type AAV) at the 5 ’ and 3’ ends of the ssDNA which fonn an energetically stable double stranded region.
  • the double stranded hairpin structures comprise multiple functions including, but not limited to, acting as an origin for DNA replication by functioning as primers for the endogenous DNA polymerase complex of the host viral replication cell.
  • the AAV particle e.g., an AAV particle (e.g., ssAAVs) described herein comprises a viral genome that is self-complementary (sc AAV).
  • the ssAAV comprises nucleic acid molecules, e.g., DNA strands, that anneal together to form double stranded DNA.
  • a scAAV allows for rapid expression in a transduced cell as it bypasses second strand synthesis.
  • the wild-type AAV viral genome further comprises nucleotide sequences for two open reading frames, one for the four non-structural Rep proteins (Rep78. Rep68, Rep52, Rep40, encoded by Rep genes) and one for the three capsid, or structural, proteins (VP1, VP2, VP3, encoded by capsid genes or Cap genes).
  • the Rep proteins are used for replication and packaging, while the capsid proteins are assembled to create the protein shell of the AAV, or AAV capsid polypeptide, e.g., an AAV capsid variant.
  • VP1 refers to amino acids 1-736
  • VP2 refers to amino acids 138-736
  • VP3 refers to amino acids 203-736.
  • VP1 is the full-length capsid sequence
  • VP2 and VP3 are shorter components of the whole.
  • the sequence in the VP3 region As a result, changes in the sequence in the VP3 region, are also changes to VP1 and VP2, however, tire percent difference as compared to tire parent sequence will be greatest for VP3 since it is the shortest sequence of the three.
  • the nucleic acid sequence encoding these proteins can be similarly described.
  • the three capsid proteins assemble to create the '‘AAV capsid” protein. While not wishing to be bound by theory, the AAV capsid protein typically comprises a molar ratio of 1: 1: 10 of VP1:VP2:VP3.
  • a viral genome of a wild-type, e.g., naturally occurring, AAV can be modified to replace the rep/cap sequences with a nucleic acid comprising a transgene encoding a payload, e.g., an antibody molecule, wherein the genetic element comprises at least one ITR region.
  • the viral genome of a recombinant AAV comprises two ITR regions, e.g.. a 5TTR or a 3TTR.
  • the rep/cap sequences can be provided in trans during production to generate AAV particles.
  • the viral genome of an AAV is comprised in an AAV vector, which further encodes a capsid protein e.g., a structural protein, wherein the capsid protein comprises a VP1 polypeptide, a VP2 polypeptide, and/or a VP3 polypeptide; and/or a Rep protein, e.g.. a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68, Rep52 protein, and/or a Rep40 protein.
  • AAV particles of the present disclosure are recombinant AAV particles which are replication defective and lacking the nucleotide sequences encoding functional Rep and Cap proteins. In some embodiments, these defective AAV particles may lack most or all parental coding sequences and carry only one or two AAV ITR sequences and the nucleic acid of interest for delivery to a cell, a tissue, an organ, or an organism.
  • the AAV particles of the disclosure comprising an AAV capsid polypeptide, and a viral genome are capable of providing, e.g., delivering, a transgene to a cell, e.g., mammalian cell ad/or a subject.
  • the recombinant AAV particles of the present disclosure are capable of vectorized delivery of a siRNA (e.g., an siRNA for targeting MAPT).
  • an AAV particle e.g., an AAV particle for the vectorized delivery of an siRNA described herein (e.g., an siRNA for targeting MAPT)
  • an AAV capsid polypeptide e.g., an AAV capsid variant.
  • the AAV capsid polypeptide allows for blood brain barrier penetration following intravenous administration.
  • the AAV capsid allows for blood brain barrier penetration following focused ultrasound (FUS). e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration.
  • FUS focused ultrasound
  • the AAV capsid e.g., AAV capsid variant allows for increased distribution to a brain region.
  • the brain region comprises a frontal cortex, sensory cortex, motor cortex, caudate, dentate nucleus, cerebellar cortex, cerebral cortex, brain stem, hippocampus, thalamus, putamen, or a combination thereof.
  • the AAV capsid e.g., AAV capsid variant allows for preferential transduction in a brain region relative to the transduction in the dorsal root ganglia (DRG).
  • DRG dorsal root ganglia
  • the AAV capsid polypeptide e.g., AAV capsid variant allows for increased distribution to a spinal cord region.
  • the spinal region comprises a cervical spinal cord region, thoracic spinal cord region, and/or lumbar spinal cord region.
  • the AAV capsid polypeptide e.g., an AAV capsid variant comprises a VOY101 capsid polypeptide, a PHPeB capsid polypeptide, an AAVPHP.B (PHP.B) capsid polypeptide, a AAVPHP.N (PHP.N) capsid polypeptide, an AAV1 capsid polypeptide, an AAV2 capsid polypeptide, an AAV5 capsid polypeptide, an AAV9 capsid polypeptide, an AAV9 K449R capsid polypeptide, an AAVrhlO capsid polypeptide, or a functional variant thereof.
  • the AAV capsid polypeptide e.g., AAV capsid variant, comprises an amino acid sequence of any of the AAV capsid polypeptides in Table 1, or an amino acid sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.
  • the nucleotide sequence encoding the AAV capsid polypeptide comprises any one of the nucleotide sequences in Table 1, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%. 80%. 85%. 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises the amino acid sequence of any of SEQ ID NOs: 1, 3, 11, 138, 12, 13. 14, 16, 18, 20, 5147, 3636, or an amino acid sequence substantially identical (e.g.. having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%. 97%. 98%. or 99% sequence identity) thereto.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises an amino acid sequence comprising at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, but no more than 30, 20, or 10 modifications, e g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1, 3, 11, 138, 12, 13. 14, 16, 18, 20, or 3636.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises an amino acid sequence encoded by the nucleotide sequence of any of SEQ ID NOs: 137, 15, 17, 19, 21, 3623, or a nucleotide sequence substantially identical (e.g., having at least 70%. 75%. 80%. 85%. 90%. 92%. 95%, 97%, 98%, or 99% sequence identity) thereto.
  • tire nucleotide sequence encoding the AAV capsid polypeptide comprises the nucleotide sequence of any of SEQ ID NOs: 137, 15, 17, 19, 21, 5148, or 3623, or a nucleotide sequence substantially identical (e.g., having at least 70%. 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.
  • the nucleotide sequence encoding the AAV capsid polypeptide, e g., the AAV capsid variant comprises a nucleotide sequence comprising at least one, two.
  • substitutions e.g., conservative substitutions
  • insertions or deletions, but no more than 30, 20, or 10 modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the nucleotide sequence of any of SEQ ID NOs: 137, 15, 17, 19, 21, or 3623.
  • the AAV capsid polypeptide e.g., the AAV capsid variant
  • the AAV capsid polypeptide e.g., the AAV capsid variant
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 137 or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.
  • the nucleotide sequence encoding the AAV capsid polypeptide e.g...
  • the AAV capsid variant comprises the nucleotide sequence of SEQ ID NO: 137 or a nucleotide sequence substantially identical (e.g., having at least 70%. 75%. 80%. 85%. 90%. 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises substitution at position K449, e.g., a K449R substitution, numbered according to SEQ ID NO: 138.
  • the AAV capsid polypeptide e.g., tire AAV capsid variant, comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises an amino acid sequence comprising at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but no more than 30, 20, or 10 modifications, e.g., substitutions (conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 11, optionally wherein position 449 is not R.
  • the capsid polypeptide comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises an amino acid sequence comprising at least one, two, or three modifications, e.g., substitutions (e.g.. conservative substitutions), but no more than 30, 20, or 10 modifications, e.g., substitutions (e.g.. conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 1.
  • tire capsid polypeptide comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.
  • the AAV capsid polypeptide e.g.. the AAV capsid variant, comprises an amino acid sequence comprising at least one. two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but no more than 30, 20, or 10 modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 3.
  • the capsid polypeptide comprises the amino acid sequence of SEQ ID NO: 5147 or an amino acid sequence substantially identical (e.g.. having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises an amino acid sequence comprising at least one, two, or three modifications, e.g., substitutions (e.g., conservative substitutions), but no more than 30, 20, or 10 modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 5147.
  • an AAV capsid variant disclosed herein comprises a modification in loop VIII of AAV9, e.g., at positions between 580-599, e.g., at positions 587, 588, 589, and/or 590, numbered relative to SEQ ID NO: 5, 8, 138 or 3636-3647.
  • loop e.g., loop VIII
  • the temr variable region e.g., variable region VIII
  • VR e g., VR-VIII
  • loop VIII comprises positions 580-599 (e.g., amino acids VATNHQSAQAQAQTGWVQNQ (SEQ ID NO: 1195)).
  • loop VIII comprises positions 582-593 (e.g., amino acids TNHQSAQAQAQT (SEQ ID NO: 1196)), numbered according to SEQ ID NO: 138.
  • loop VIII comprises positions 587- 593 (e.g., amino acids AQAQAQT (SEQ ID NO: 1197)), numbered according to SEQ ID NO: 138.
  • loop VIII comprises positions 587-590 (e.g., amino acids AQAQ (SEQ ID NO: 5026)), numbered according to SEQ ID NO: 138.
  • loop VIII or variable region VIII (VR-VIII) is as described in DiMattia et al.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises a peptide comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1262).
  • the peptide is present immediately subsequent to position 588, relative to a reference sequence numbered according to SEQ ID NO: 138.
  • the capsid polypeptide comprises the amino acid substitutions of A587D and Q588G, numbered according to SEQ ID NO: 138.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises the amino acid substitution of K449R. numbered according to SEQ ID NO: 138; and a peptide comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1262), wherein the peptide is present immediately subsequent to position 588, relative to a reference sequence numbered according to SEQ ID NO: 138.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises the amino acid substitution of K449R, numbered according to SEQ ID NO: 138; an peptide comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1262), wherein the insert is present immediately subsequent to position 588, relative to a reference sequence numbered according to SEQ ID NO: 138; and the amino acid substitutions of A587D and Q588G. numbered according to SEQ ID NO: 138.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises a peptide comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1262), wherein the insert is present immediately subsequent to position 588, relative to a reference sequence numbered according to SEQ ID NO: 138; and the amino acid substitutions of A587D and Q588G, numbered according to SEQ ID NO: 138.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises at least 3, 4, 5, 6, 7, 8, or 9 consecutive amino acids from the amino acid sequence of PLNGAVHLY (SEQ ID NO: 3648).
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises the amino acid sequence of PLNGAVHLY (SEQ ID NO: 3648), an amino acid sequence comprising at least one, two, or three but no more than four modifications, e g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the amino acid sequence of PLNGAVHLY (SEQ ID NO: 3648), or an amino acid sequence comprising at least one, two. or three but no more than four different amino acids relative to the amino acid sequence of PLNGAVHLY (SEQ ID NO: 3648), optionally wherein position 7 is H.
  • the amino acid sequence is present in loop VIII.
  • the amino acid sequence is present immediately subsequent to position 586, relative to a reference sequence numbered according to the amino acid sequence of SEQ ID NO: 138. In some embodiments, the amino acid sequence replaces positions replaces positions 587 and 588 (e.g., A587 and Q 588), numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence is present at immediately subsequent to position 586 and replaces positions 587 and 588 (e.g., A587 and Q 588), numbered according to SEQ ID NO: 138. [0056] In some embodiments, the 3 consecutive amino acids comprise PLN. In some embodiments, the 4 consecutive amino acids comprise PLNG (SEQ ID NO: 3678).
  • the 5 consecutive amino acids comprise PLNGA (SEQ ID NO: 3679). In some embodiments, the 6 consecutive amino acids comprise PLNGAV (SEQ ID NO: 3680). In some embodiments, the 7 consecutive amino acids comprise PLNGA VH (SEQ ID NO: 3681). In some embodiments, the 8 consecutive amino acids comprise PLNGA VHL (SEQ ID NO: 3682). In some embodiments, the 9 consecutive amino acids comprise PLNGA VHLY (SEQ ID NO: 3648).
  • tire four consecutive amino acids comprise NGAV (SEQ ID NO: 3683). In some embodiments, the four consecutive amino acids comprise GAVH (SEQ ID NO: 3684). In some embodiments, the five consecutive amino acids comprise NGAVH (SEQ ID NO: 3685). In some embodiments, the five consecutive amino acids comprise GA VHL (SEQ ID NO: 3686). In some embodiments, the five consecutive amino acids comprise AVHLY (SEQ ID NO: 3687). In some embodiments, the six consecutive amino acids comprise NGAVHL (SEQ ID NO: 3688). In some embodiments, the seven consecutive amino acids comprise NGAVHLY (SEQ ID NO: 3689).
  • the AAV capsid polypeptide e.g., the AAV capsid variant (e g., an AAV capsid variant described herein), comprises an amino acid sequence encoded by the nucleotide sequence of CCGCTTAATGGTGCCGTCCATCTTTAT (SEQ ID NO: 3660), or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.
  • the AAV capsid e.g., an AAV capsid variant described herein, comprises an amino acid sequence encoded by a nucleotide sequence comprising at least one, two, three, four, five, six, or seven modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, but no more than ten modifications, e.g., substitutions (e.g., conservative substitutions), insertions, or deletions, relative to the nucleotide sequence of CCGCTTAATGGTGCCGTCCATCTTTAT (SEQ ID NO: 3660).
  • the AAV capsid polypeptide e.g., the AAV capsid variant (e.g., an AAV capsid variant described herein), comprises an amino acid sequence encoded by a nucleotide sequence comprising at least one, two, three, four, five, six, or seven, but no more than ten different nucleotides relative to the nucleotide sequence of CCGCTTAATGGTGCCGTCCATCTTTAT (SEQ ID NO: 3660).
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises the amino acid P at position 587, the amino acid L at position 588, and the amino acid sequence NGAVHLY (SEQ ID NO: 3689), which is present immediately subsequent to position 588, corresponding to or numbered according to SEQ ID NO: 3636.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, e.g., an AAV capsid variant described herein, comprises the amino acid sequence of SEQ ID NO: 3636. or an amino acid sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, e.g., an AAV capsid variant described herein, comprises the amino acid sequence of SEQ ID NO: 3636, or an amino acid sequence at least 95% identical thereto.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, e.g., an AAV capsid variant described herein, comprises the amino acid sequence of SEQ ID NO: 3636, or an amino acid sequence at least 99% identical thereto.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, e.g., an AAV capsid variant described herein, comprises an amino acid sequence comprising at least one, two, or three modifications, substitutions (e.g., conservative substitutions), insertions, or deletions, but not more than 30, 20 or 10 modifications, substitutions (e.g., conservative substitutions), insertions, or deletions relative to the amino acid sequence of SEQ ID NO: 3636.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, e.g., an AAV capsid variant described herein, comprises an amino acid sequence having at least one. two, or three but no more than 30, 20. or 10 different amino acids relative to the amino acid sequence of SEQ ID NO: 3636.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises the amino acid sequence corresponding to positions 138-743, e.g., a VP2, of SEQ ID NO: 3636, or a sequence with at least 80% (e.g., at least about 85, 90. 95, 96, 97, 98, or 99%) sequence identity thereto.
  • the AAV capsid variant comprises the amino acid sequence corresponding to positions 203- 743, e.g., a VP3, of SEQ ID NO: 3636, or a sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises the amino acid sequence corresponding to positions 138-736, e.g., a VP2, of SEQ ID NO: 138. or a sequence with at least 80% (e.g...
  • the AAV capsid variant comprises the amino acid sequence corresponding to positions 203-736. e.g., a VP3. of SEQ ID NO: 138. or a sequence with at least 80% (e.g.. at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.
  • the amino acid sequence is present immediately subsequent to position 586, numbered according to any one of SEQ ID NO: 138 or 3636, optionally wherein the amino acid replaces positions 587 and 588 (e.g., A587 and Q588), numbered according to SEQ ID NO: 138.
  • the amino acid sequence corresponds to positions 587-595 of SEQ ID NO: 3636.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises one or two, but no more than three different amino acids (e.g., substitutions, e.g., conservative substitutions) relative to the amino acid sequence of PLNGAVHLY (SEQ ID NO: 3648), wherein the AAV capsid variant comprises (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or 3636; (b) a VP2 protein comprising the amino acid sequence of positions 138-736 of SEQ ID NO: 138 or positions 138-743 of SEQ ID NO: 5, 8, or 3636; (c) a VP3 protein comprising the amino acid sequence of positions 203-736 of SEQ ID NO: 138 or positions 203-743 of SEQ ID NO: 5, 8.
  • substitutions e.g., conservative substitutions
  • amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98, or 99%) sequence identity to any of the amino acid sequences in (a)-(c).
  • amino acid sequence is present immediately subsequent to position 586, numbered according to any one of SEQ ID NO: 138 or 3636, optionally wherein the amino acid replaces positions 587 and 588 (e.g., A587 and Q588), numbered according to SEQ ID NO: 138.
  • the amino acid sequence corresponds to positions 587-595 of SEQ ID NO: 3636.
  • the AAV capsid polypeptide e.g., the AAV capsid variant
  • the amino acid sequence is present immediately subsequent to position 586, numbered according to any one of SEQ ID NO: 138 or 3636, optionally wherein the amino acid replaces positions 587 and 588 (e.g., A587 and Q588), numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence corresponds to positions 587-595 of SEQ ID NO: 3636.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises an amino acid sequence comprising at least 5, 6, 7. 8. or 9 consecutive amino acids from the amino acid sequence of PLNGAVHLY (SEQ ID NO: 3648), wherein: (i) the 5 consecutive amino acids comprise PLNGA (SEQ ID NO: 3679); (ii) the 6 consecutive amino acids comprise PLNGAV (SEQ ID NO: 3680); (iii) the 7 consecutive amino acids comprise PLNGA VH (SEQ ID NO: 3681); (iv) the 8 consecutive amino acids comprise PLNGA VHL (SEQ ID NO: 3682); or (v) the 9 consecutive amino acids comprise PLNGAVHLY (SEQ ID NO: 3648), wherein the AAV capsid variant comprises: (a) a VP1 protein comprising the amino acid sequence of SEQ ID NO: 138 or SEQ ID NO: 3636; (b) a VP2 protein comprising the amino acid sequence of
  • the amino acid sequence is present immediately subsequent to position 586, numbered according to any one of SEQ ID NO: 138 or 3636, optionally wherein the amino acid replaces positions 587 and 588 (e.g.. A587 and Q588). numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence corresponds to positions 587-595 of SEQ ID NO: 3636.
  • the AAV capsid polypeptide e.g., the AAV capsid variant, comprises an amino acid sequence comprising at least 5, 6, 7, 8. or 9 consecutive amino acids from the amino acid sequence of PLNGAVHLY (SEQ ID NO: 3648), wherein: (i) the 5 consecutive amino acids comprise PLNGA (SEQ ID NO: 3679): (ii) the 6 consecutive amino acids comprise PLNGAV (SEQ ID NO: 3680); (iii) the 7 consecutive amino acids comprise PLNGA VH (SEQ ID NO: 3681); (iv) the 8 consecutive amino acids comprise PLNGA VHL (SEQ ID NO: 3682); or (v) the 9 consecutive amino acids comprise PLNGA VHLY (SEQ ID NO: 3648), wherein the AAV capsid variant comprises the amino acid sequence of any one of SEQ ID NOs: 5, 8, or 3636 or an amino acid sequence with at least 90% (e.g., at least about 95, 96, 97, 98
  • the amino acid sequence is present immediately subsequent to position 586, numbered according to any one of SEQ ID NO: 138 or 3636, optionally wherein the amino acid replaces positions 587 and 588 (e.g., A587 and Q588), numbered according to SEQ ID NO: 138. In some embodiments, the amino acid sequence corresponds to positions 587-595 of SEQ ID NO: 3636.
  • the nucleotide sequence encoding an AAV capsid polypeptide e.g., an AAV capsid variant, described herein comprises the nucleotide sequence of SEQ ID NO: 3623, or a nucleotide sequence with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.
  • nucleotide sequence encoding the AAV capsid variant comprises a nucleotide sequence comprising at least one, two or three modifications, e.g., substitutions, insertions, or deletions, but not more than 30, 20 or 10 modifications, e.g., substitutions, insertions, or deletions, relative to the nucleotide sequence of SEQ ID NO: 3623.
  • the nucleotide sequence encoding the AAV capsid variant comprises a nucleotide sequence comprising at least one, two or three, but not more than 30. 20 or 10 different nucleotides, relative to the nucleotide sequence of SEQ ID NO: 3623.
  • the nucleic acid sequence encoding an AAV capsid polypeptide, e.g., an AAV capsid variant, described herein is codon optimized.
  • an AAV capsid polypeptide e.g.. an AAV capsid variant, described herein has an increased tropism for a CNS cell or tissue, e.g.. a brain cell, brain tissue, spinal cord cell, or spinal cord tissue, relative to the tropism of a reference sequence comprising the amino acid sequence of SEQ ID NO: 138.
  • an AAV capsid polypeptide e.g., an AAV capsid variant
  • an AAV capsid variant comprises a modification, e.g.. substitution (e.g.. conservative substitution), insertion, or deletion, that results in reduced tropism (e.g., de-targeting) and/or activity in the liver.
  • the reduced tropism in the liver is compared to an otherwise similar capsid that does not comprise the modification, e.g., a wild-type capsid polypeptide.
  • an AAV capsid variant described comprises a modification, e.g., substitution (e.g., conservative substitution), insertion, or deletion, that results in one or more of the following properties: (1) reduced tropism in the liver; (2) de-targeted expression in the liver; (3) reduced activity in the liver; and/or (4) reduced binding to galactose.
  • the reduction in any one, or all of properties ( 1 )-(3) is compared to an otherwise similar AAV capsid variant that does not comprise the modification.
  • Exemplary modifications are provided in WO 2018/1 19330; Pueuerla et al. (201 1) Mol. Ther. 19(6): 1070-1078; Adachi et al.
  • the AAV capsid variant comprises a modification e.g., substitution (e.g., conservative substitution), insertion, or deletion, at position N470 (e.g., N470A), D271 (e.g., D271A).
  • N272 e.g., N272A
  • Y446 e.g., Y446A
  • N498 e.g., N498Y or N498I
  • W503 e.g., W503R or W503A
  • L620 e.g., L620F
  • SEQ ID NO: 138 a reference sequence numbered according to SEQ ID NO: 138.
  • the AAV capsid variant comprises one, two, three, four, five or all of an amino acid other than N at position 470 (e.g., A), an amino acid other than D at position 271 (e.g., A), an amino acid other than N at position 272 (e.g., A), an amino acid other than Y at position 446 (e.g., A), and amino acid other than N at position 498 (e.g., Y or I), and amino acid other than W at position 503 (e.g., R or A), and amino acid other than L at position 620 (e.g., F), relative to a reference sequence numbered according to SEQ ID NO: 138.
  • the AAV capsid variant comprises a modification e.g., substitution (e.g., conservative substitution), insertion, or deletion, at position N470 (e.g., N470A), D271 (e.g., D271A), N272 (e.g., N272A), Y446 (e.g., Y446A), and W503 (e.g., W503R or W03A), relative to a reference sequence numbered according to SEQ ID NO: 138.
  • the AAV capsid variant comprises a modification e.g.. substitution (e.g.. conservative substitution), insertion, or deletion, at N498 (e.g., N498Y) and L620 (e.g., L620F).
  • an AAV capsid variant comprised herein comprises a modification as described in Adachi ct al. (2014) Nature Communications 5(3075), DOI: 10. 1038/ncomms4075, the contents of which are hereby incorporated by reference in its entirety.
  • Exemplary modifications that alter or do not alter tissue transduction in at least the brain, liver, heart, lung, and/or kidney can be found in Supplementary- Data 2 showing the AAV Barcode-Seq data obtained with AAV9-AA-VBCLib of Adachi et al. (supra), the contents of which are hereby incorporated by reference in its entirety.
  • an, AAV capsid polypeptide, e.g., an AAV capsid variant, of tire present disclosure is isolated, e.g., recombinant.
  • a polynucleotide encoding an AAV capsid polypeptide, e g., an AAV capsid variant, of the present disclosure is isolated, e.g., recombinant.
  • the present disclosure refers to structural capsid proteins (including VP1, VP2 and VP3) which are encoded by capsid (Cap) genes. These capsid proteins form an outer protein structural shell (i.e. capsid) of a viral vector such as AAV.
  • VP capsid proteins synthesized from Cap polynucleotides generally include a methionine as the first amino acid in the peptide sequence (Metl), which is associated with the start codon (AUG or ATG) in the corresponding Cap nucleotide sequence.
  • a first-methionine (Metl) residue or generally any first amino acid (AA1) to be cleaved off after or during polypeptide synthesis by protein processing enzymes such as Met-aminopeptidases.
  • Uris “Met/AA-clipping” process often correlates with a corresponding acetylation of the second amino acid in the polypeptide sequence (e.g., alanine, valine, serine, threonine, etc.). Met-clipping commonly occurs with VP1 and VP3 capsid proteins but can also occur with VP2 capsid proteins.
  • Met/AA-clipping is incomplete, a mixture of one or more (one, two or three) VP capsid proteins comprising the viral capsid may be produced, some of which may include a Metl/AAl amino acid (Met+/AA+) and some of which may lack a Metl/AAl amino acid as a result of Met/AA-clipping (Met-/AA- ).
  • Met/AA-clipping in capsid proteins see Jin, et al. Direct Liquid Chromatography/Mass Spectrometry Analysis for Complete Characterization of Recombinant Adeno- Associated Virus Capsid Proteins. Hum Gene Ther Methods. 2017 Oct. 28(5):255-267; Hwang, et al. N- Terminal Acetylation of Cellular Proteins Creates Specific Degradation Signals. Science. 2010 February 19. 327(5968): 973-977; the contents of which are each incorporated herein by reference in its entirety.
  • references to capsid proteins is not limited to either clipped (Met-/AA-) or unclipped (Met+/AA+) and may, in context, refer to independent capsid proteins, viral capsids comprised of a mixture of capsid proteins, and/or polynucleotide sequences (or fragments thereof) which encode, describe, produce or result in capsid proteins of the present disclosure.
  • a direct reference to a “capsid protein” or “capsid polypeptide” may also comprise VP capsid proteins which include a Metl/AAl amino acid (Met+/AA+) as well as corresponding VP capsid proteins which lack the Metl/AAl amino acid as a result of Met/AA-clipping (Met-/AA-).
  • a reference to a specific SEQ ID NO: (whether a protein or nucleic acid) which comprises or encodes, respectively, one or more capsid proteins which include a Metl/AAl amino acid (Met+/AA+) should be understood to teach the VP capsid proteins which lack the Metl/AAl amino acid as upon review of the sequence, it is readily apparent any sequence which merely lacks the first listed amino acid (whether or not Metl/AAl).
  • reference to a VP1 polypeptide sequence which is 736 amino acids in length and which includes a “Metl” amino acid (Met+) encoded by the AUG/ATG start codon may also be understood to teach a VP1 polypeptide sequence which is 735 amino acids in length and which does not include the “Metl” amino acid (Met-) of the 736 amino acid Met+ sequence.
  • VP1 polypeptide sequence which is 736 amino acids in length and which includes an “AA1” amino acid (AA1+) encoded by any NNN initiator codon may also be understood to teach a VP1 polypeptide sequence which is 735 amino acids in length and which docs not include the “AA1” amino acid (AA1-) of the 736 amino acid AA1+ sequence.
  • references to viral capsids formed from VP capsid proteins can incorporate VP capsid proteins which include a Metl/AAl amino acid (Met+/AA1+), corresponding VP capsid proteins which lack the Metl/AAl amino acid as a result of Met/AAl -clipping (Met-/AA1-), and combinations thereof (Met+/AA1 + and Met-/AA1-).
  • an AAV capsid serotype can include VP1 (Met+/AA1+), VP1 (Met- /AA1-), or a combination of VP1 (Met+/AA1+) and VP1 (Met-/AA1-).
  • An AAV capsid serotype can also include VP3 (Met+/AA1+), VP3 (Met-/AA1-), or a combination ofVP3 (Met+/AA1+) and VP3 (Met-/AA1- ); and can also include similar optional combinations of VP2 (Met+/AA1) and VP2 (Met-/AA1-).
  • polynucleotide sequences encoding any of the AAV capsid variants described above and AAV particles, vectors, and cells comprising the same Viral Genome
  • an AAV particle of the present disclosure e.g., an AAV particle comprising an AAV capsid polypeptide, e.g., an AAV capsid variant described herein, comprises a viral genome which encodes a an agent for targeting MAPT, e.g., a siRNA duplex for targeting MAPT or a modulatory polynucleotide encoding a siRNA duplex for targeting MAPT.
  • a an agent for targeting MAPT e.g., a siRNA duplex for targeting MAPT or a modulatory polynucleotide encoding a siRNA duplex for targeting MAPT.
  • an AAV particle as described herein comprising an AAV capsid polypeptide, e.g., AAV capsid variant, described herein may be used for the delivery of a viral genome to a tissue (e.g., CNS, DRG. and/or muscle).
  • an AAV particle comprising an AAV capsid polypeptide, e.g., an AAV capsid variant, described herein can be used for delivery of a viral genome to a tissue or cell, e.g., CNS, DRG, or muscle cell or tissue.
  • an AAV particle of the present disclosure is a recombinant AAV particle.
  • an AAV particle of tire present disclosure is an isolated AAV particle.
  • the AAV particles described herein are used to deliver the agent to target MAPT (e.g., a MAPT targeting siRNA duplex or a modulatory polynucleotide encoding a siRNA duplex to cells of the CNS, after intravenous delivery.
  • MAPT e.g., a MAPT targeting siRNA duplex or a modulatory polynucleotide encoding a siRNA duplex to cells of the CNS
  • a viral genome of an AAV particle comprising an AAV capsid polypeptide comprises a nucleic acid comprising a transgene encoding the agent to target MAPT (e.g., a MAPT targeting siRNA duplex or a modulatory polynucleotide encoding a siRNA duplex (e.g., a siRNA duplex for targeting MAPT)).
  • the viral genome comprises an inverted terminal repeat (ITR) sequence.
  • the viral genome comprises two ITR sequences, e.g., one at the 5’ end of the viral genome (e.g., 5’ relative to the encoded payload) and one at the 3’ end of the viral genome (e.g., 3’ relative to the encoded payload).
  • a viral genome of the AAV particles described herein may comprise a regulatory element (e.g., promoter), untranslated regions (UTR), a miR binding site a polyadenylation sequence (polyA), a filler or stuffer sequence, an intron, and/or a linker sequence, e.g., for enhancing transgene expression.
  • the viral genome components are selected and/or engineered for expression of an agent for targeting MAPT (e.g., a MAPT targeting siRNA duplex or a modulatory polynucleotide encoding a siRNA duplex (e.g., a siRNA duplex for targeting MAPT)) in a target tissue (e.g., a CNS tissue, e.g., a brain tissue or a spinal cord tissue), or a target cell (e.g., a cell of tire CNS, e.g., a brain cell or a spinal cord cell).
  • a target tissue e.g., a CNS tissue, e.g., a brain tissue or a spinal cord tissue
  • a target cell e.g., a cell of tire CNS, e.g., a brain cell or a spinal cord cell.
  • ITRs Inverted Terminal Repeats
  • the viral genome comprises an ITR and a transgene encoding a payload.
  • the viral genome has two ITRs.
  • the two ITRs flank the nucleotide sequence encoding the payload at the 5’ and 3’ ends.
  • the ITRs function as origins of replication comprising recognition sites for replication.
  • the ITRs comprise sequence regions which can be complementary and symmetrically arranged.
  • the ITRs incorporated into viral genomes as described herein may be comprised of naturally occurring polynucleotide sequences or recombinantly derived polynucleotide sequences.
  • the ITR may be of the same serotype as the capsid polypeptide, e.g., capsid variant, selected from any of the known serotypes, or a variant thereof. In some embodiments, the ITR may be of a different serotype than the capsid.
  • tire viral genome comprises two ITR sequence regions, wherein the ITRs are of the same serotype as one another. In another embodiment, the viral genome comprises two ITR sequence regions, wherein the ITRs are of different serotypes. Non-limiting examples include zero, one or both of the ITRs having tire same serotype as the capsid. In one embodiment both ITRs of tire viral genome of the AAV particle are AAV2 ITRs.
  • the ITR comprises the nucleotide sequence of SEQ ID NO: 5197, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%. or 99% identical thereto.
  • the ITR comprises the nucleotide sequence of SEQ ID NO: 5200, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • an AAV viral genome comprises an ITR comprising the nucleotide sequence of SEQ ID NO: 5197, or a nucleotide sequence at least 70%, 75%, 80%, 85%. 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and an ITR comprising the nucleotide sequence of SEQ ID NO: 5200, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the ITR comprises the nucleotide sequence of SEQ ID NO: 4469, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%. or 99% identical thereto.
  • the ITR comprises tire nucleotide sequence of SEQ ID NO: 4470, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%. or 99% identical thereto.
  • an AAV viral genome comprises an ITR comprising the nucleotide sequence of SEQ ID NO: 4469.
  • nucleotide sequence at least 70%, 75%, 80%, 85%. 90%. 92%. 95%. 96%. 97%. 98%, or 99% identical thereto, and an ITR comprising the nucleotide sequence of SEQ ID NO: 4470, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the viral genome comprises at least one element to enhance the payload target specificity and expression (See e.g., Powell et al. Viral Expression Cassette Elements to Enhance Transgene Target Specificity and Expression in Gene Therapy, 2015; the contents of which are herein incorporated by reference in their entirety).
  • elements to enhance payload target specificity and expression include promoters, endogenous miRNAs, post-transcriptional regulatory elements (PREs), polyadenylation (PolyA) signal sequences and upstream enhancers (USEs), CMV enhancers and introns.
  • an AAV particle comprising an AAV capsid variant described herein comprises a viral genome comprising a nucleic acid comprising a transgene encoding a payload, wherein the transgene is operably linked to a promoter.
  • the promoter is a species-specific promoter, an inducible promoter, a tissue-specific promoter, or a cell cycle-specific promoter (e g., a promoter as described in Parr et al., Nat. Med.3:l 145-9 (1997); the contents of which are herein incorporated by reference in their entirety).
  • the promoter may be naturally occurring or non-naturally occurring.
  • Non- limiting examples of promoters include those derived from viruses, plants, mammals, or humans.
  • the promoters may be those derived from human cells or systems.
  • the promoter may be truncated or mutated, e.g., a promoter variant.
  • the promoter is a ubiquitous promoter, e g ., capable of expression in multiple tissues.
  • the promoter is a human elongation factor la-subunit (EFla) promoter, the cytomegalovirus (CMV) immediate-early enhancer and/or promoter, the chicken [3-actin (CBA) promoter and its derivative CAG, P glucuronidase (GUSB) promoter, or ubiquitin C (UBC) promoter.
  • EFla human elongation factor la-subunit
  • CMV cytomegalovirus
  • CBA chicken [3-actin
  • GUSB P glucuronidase
  • UBC ubiquitin C
  • the promoter is a cell or tissue specific promoter, e.g., capable of expression in tissues or cells of the central or peripheral nervous systems, targeted regions within (e.g., frontal cortex), and/or sub-sets of cells therein (e.g., excitatory neurons).
  • the promoter is a cell-type specific promoters capable of expression of a payload in excitatory' neurons (e.g., glutamatergic), inhibitory neurons (e.g., GABA-crgic), neurons of the sympathetic or parasympathetic nervous system, sensory’ neurons, neurons of the dorsal root ganglia, motor neurons, or supportive cells of the nervous systems such as microglia, glial cells, astrocytes, oligodendrocytes, and/or Schwann cells.
  • excitatory' neurons e.g., glutamatergic
  • inhibitory neurons e.g., GABA-crgic
  • the promoter is a liver specific promoter (e.g., hAAT, TBG), skeletal muscle specific promoter (e.g., desmin, MCK, C512), B cell promoter, monocyte promoter, leukocyte promoter, macrophage promoter, pancreatic acinar cell promoter, endothelial cell promoter, lung tissue promoter, and/or cardiac or cardiovascular promoter (e.g., aMHC. cTnT, and CMV-MLC2k).
  • a liver specific promoter e.g., hAAT, TBG
  • skeletal muscle specific promoter e.g., desmin, MCK, C512
  • B cell promoter e.g., monocyte promoter, leukocyte promoter, macrophage promoter, pancreatic acinar cell promoter, endothelial cell promoter, lung tissue promoter, and/or cardiac or cardiovascular promoter (e.g., aMHC. cTnT, and CMV-MLC
  • the promoter is a tissue-specific promoter for payload expression in a tissue or cell of the central nervous system.
  • the promoter is a synapsin (Syn) promoter, glutamate vesicular transporter (VGLUT) promoter, vesicular GABA transporter (VGAT) promoter, parvalbumin (PV) promoter, sodium channel Na v 1.8 promoter, tyrosine hydroxylase (TH) promoter, choline acetyltransferase (ChaT) promoter, methyl-CpG binding protein 2 (MeCP2) promoter, Ca 2+ /calmodulin- dependent protein kinase II (CaMKII) promoter, metabotropic glutamate receptor 2 (mGluR2) promoter, neurofilament light chain (NFL) or heavy chain (NFH) promoter, neuron-specific enolase (NSE) promoter, [3- globin minigene
  • the promoter is a cell-type specific promoter capable of expression in an astrocyte, e.g., a glial fi bri 11 ary acidic protein (GFAP) promoter and a EAAT2 promoter, or a fragment thereof.
  • the promoter is a cell-type specific promoter capable of expression in an oligodendrocyte, e.g., a myelin basic protein (MBP) promoter or a fragment thereof.
  • the promoter is a GFAP promoter. In some embodiments, the promoter is a synapsin (syn or syn I ) promoter, or a fragment thereof.
  • the promoter comprises a CBA promoter or a variant thereof, e.g., a functional variant thereof.
  • the promoter comprises the nucleotide sequence of SEQ ID NO: 5199. or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%. 97%. 98%. or 99% identical thereto.
  • the AAV viral genome comprises an enhancer.
  • the enhancer comprises a CMVie enhancer, or a variant thereof.
  • tire enhancer comprises the nucleotide sequence of SEQ ID NO: 4471. or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%. or 99% identical thereto.
  • the enhancer comprises the nucleotide sequence of SEQ ID NO: 4472, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the AAV viral genome comprises an enhancer and a promoter.
  • the enhancer comprises a CMVie enhancer and the promoter comprises a CBA promoter.
  • the enhancer and the promoter comprise the nucleotide sequence of SEQ ID NO: 4474. or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • the promoter comprises an insulin promoter or a fragment thereof.
  • the viral genome comprises a ubiquitous promoter.
  • ubiquitous promoters include CMV, CBA (including derivatives CAG, CB6, CBh, etc.), EF-la, PGK, UBC, GUSB (hGBp), and UCOE (promoter of HNRPA2B1-CBX3).
  • the viral genome comprises an EF-la promoter or EF-la promoter variant, e.g., as provided in Table 2.
  • the EF-la promoter comprises the nucleotide sequence of any one of SEQ ID NOs: 1874-1889 or any of the sequences provided in Table 40, a nucleotide sequence comprising at least one, two, or three but no more than four modifications, e.g., substitutions, relative to the nucleotide sequence of SEQ ID NOs: 1874-1889 or any of tire sequences provided in Table 40, or a nucleotide sequence with at least 80% (e.g., 85%, 90%, 95%, 96%, 97%. 98%. or 99%) sequence identity to any one of SEQ ID NOs: 1874-1889 or any of the sequences provided in Table 2.
  • the viral genome comprises an element to enhance the payload target specificity and expression (See e.g., Powell et al. Viral Expression Cassette Elements to Enhance Transgene Target Specificity and Expression in Gene Therapy, Discov. Med. 2015, 19(102): 49-57; the contents of which are herein incorporated by reference in their entirety), such as an intron.
  • Non-limiting examples of introns include, MVM (67-97 bps), F.IX truncated intron 1 (300 bps),
  • the intron comprises a human beta-globin intron or a variant thereof.
  • the intron comprises the nucleotide sequence of SEQ ID NO: 4475, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • UTRs Untranslated Regions
  • a wild type untranslated region (UTR) of a gene is transcribed but not translated.
  • the 5’ UTR starts at the transcription start site and ends at the start codon and the 3’ UTR starts immediately following the stop codon and continues until the termination signal fortranscription.
  • UTRs features typically found in abundantly expressed genes of specific target organs may be engineered into UTRs to enhance the stability and protein production.
  • a 5’ UTR from mRNA normally expressed in the liver e.g., albumin, serum amyloid A. Apolipoprotein A/B/E, transferrin, alpha fetoprotein, erythropoietin, or Factor VIII
  • albumin e.g., albumin, serum amyloid A.
  • Apolipoprotein A/B/E e.g., transferrin, alpha fetoprotein, erythropoietin, or Factor VIII
  • AAV particles of the disclosure may be used in the viral genomes of the AAV particles of the disclosure to enhance expression in hepatic cell lines or liver.
  • the viral genome encoding a transgene described herein comprises a Kozak sequence.
  • wild-type 5' untranslated regions include features that play roles in translation initiation.
  • Kozak sequences which are commonly known to be involved in the process by which the ribosome initiates translation of many genes, are usually included in 5’ UTRs.
  • Kozak sequences have the consensus CCR(A/G)CCAUGG. where R is a purine (adenine or guanine) three bases upstream of the start codon (ATG), which is followed by another ’G 1 .
  • the 5'UTR in the viral genome includes a Kozak sequence.
  • the 5'UTR in the viral genome does not include a Kozak sequence.
  • AU rich elements can be separated into three classes (Chen ct al, 1995, the contents of which arc herein incorporated byreference in their entirety): Class I AREs, such as, but not limited to, c-Myc and MyoD, contain several dispersed copies of an AUUUA motif within U-rich regions. Class II AREs.
  • GM- CSF and TNF-a possess two or more overlapping UUAUUUA(U/A)(U/A) nonamers.
  • Class III ARES such as, but not limited to, c-Jun and Myogenin, are less well defined. These U rich regions do not contain an AUUUA motif.
  • Most proteins binding to the AREs are known to destabilize the messenger, whereas members of the ELAV family, most notably HuR, have been documented to increase the stability of mRNA.
  • HuR binds to AREs of all the three classes. Engineering the HuR specific binding sites into the 3' UTR of nucleic acid molecules will lead to HuR binding and thus, stabilization of the message in vivo.
  • AREs 3' UTR AU rich elements
  • AREs 3' UTR AU rich elements
  • polynucleotides When engineering specific polynucleotides, e.g., payload regions of viral genomes, one or more copies of an ARE can be introduced to make polynucleotides less stable and thereby curtail translation and decrease production of the resultant protein.
  • AREs can be identified and removed or mutated to increase the intracellular stability and thus increase translation and production of the resultant protein.
  • the 3’ UTR of the viral genome may include an oligo(dT) sequence for templated addition of a poly -A tail.
  • any UTR from any gene known in the art may be incorporated into the viral genome of the AAV particle. These UTRs, or portions thereof, may be placed in the same orientation as in the gene from which they were selected or they may be altered in orientation or location.
  • the UTR used in the viral genome of the AAV particle may be inverted, shortened, lengthened, or made with one or more other 5' UTRs or 3' UTRs known in the art.
  • the term ‘"altered,” as it relates to a UTR means that the UTR has been changed in some way in relation to a reference sequence.
  • a 3' or 5' UTR may be altered relative to a wild type or native UTR by the change in orientation or location as taught above or may be altered by the inclusion of additional nucleotides, deletion of nucleotides, swapping or transposition of nucleotides.
  • the viral genome of the AAV particle comprises at least one artificial UTR, which is not a variant of a wild type UTR.
  • the viral genome of the AAV particle comprises UTRs which have been selected from a family of transcripts whose proteins share a common function, structure, feature, or property.
  • Viral Genome Component miR Binding Site
  • Tissue- or cell-specific expression of the AAV viral particles of the invention can be enhanced by introducing tissue- or cell-specific regulatory sequences, e.g., promoters, enhancers, microRNA binding sites, e.g., a detargeting site.
  • tissue- or cell-specific regulatory sequences e.g., promoters, enhancers, microRNA binding sites, e.g., a detargeting site.
  • an encoded miR binding site can modulate, e.g., prevent, suppress, or otherwise inhibit, the expression of a gene of interest on the viral genome of the invention, based on the expression of the corresponding endogenous microRNA (rniRNA) or a corresponding controlled exogenous miRNA in a tissue or cell, e.g. , a non-targeting cell or tissue.
  • a miR binding site modulates, e.g., reduces, expression of the payload encoded by a viral genome of an AAV particle described herein in a cell or tissue where the corresponding mRNA is expressed.
  • the miR binding site modulates, e.g., reduces, expression of the encoded GBA protein in a cell or tissue of the DRG, liver, hematopoietic lineage, or a combination thereof.
  • the viral genome of an AAV particle described herein comprises a nucleotide sequence encoding a microRNA binding site, e.g. , a detargeting site.
  • the viral genome of an AAV particle described herein comprises a nucleotide sequence encoding a miR binding site, a microRNA binding site series (miR BSs), or a reverse complement thereof.
  • the nucleotide sequence encoding the miR binding site series or the miR binding site is located in the 3 ’-UTR region of the viral genome (e.g., 3' relative to the nucleic acid sequence encoding a payload), e.g., before the polyA sequence, 5 ’-UTR region of the viral genome (e.g., 5’ relative to the nucleic acid sequence encoding a payload), or both.
  • the encoded miR binding site series comprise at least 1-5 copies, e.g., at least 1-3, 2-4, 3-5, 1, 2, 3, 4, 5 or more copies of a miR binding site (miR BS). In some embodiments, the encoded miR binding site series comprises 4 copies of a miR binding site. In some embodiments, all copies are identical, e.g., comprise the same miR binding site. In some embodiments, the miR binding sites within the encoded miR binding site series are continuous and not separated by a spacer. In some embodiments, the miR binding sites within an encoded miR binding site series are separated by a spacer, e.g., a non-coding sequence.
  • the spacer is about 1 to 6 nucleotides or about 5 to 10 nucleotides, e.g., about 7-8 nucleotides, nucleotides in length. In some embodiments, the spacer is about 8 nucleotides in length. In some embodiments, the spacer sequence comprises one or more of (i) GGAT; (ii) CACGTG; (iii) GCATGC, or a repeat of one or more of (i)-(iii) . In some embodiments, the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one. two, or three modifications, but no more than four modifications of GATAGTTA.
  • the encoded miR binding site series comprise at least 1-5 copies, e.g., at least 1-3, 2-4, 3-5, 1, 2, 3, 4, 5 or more copies of a miR binding site (miR BS). In some embodiments, at least 1, 2, 3, 4, 5, or all of the copies are different, e.g., comprise a different miR binding site.
  • the miR binding sites within the encoded miR binding site series are continuous and not separated by a spacer. In some embodiments, the miR binding sites within an encoded miR binding site series are separated by a spacer, e.g.. a non-coding sequence.
  • the spacer is about 1 to 6 nucleotides or about 5 to 10 nucleotides, e.g., about 7-8 nucleotides or about 8 nucleotides, in length.
  • the spacer sequence comprises one or more of (i) GGAT; (ii) CACGTG; (iii) GCATGC, or a repeat of one or more of (i)-(iii).
  • the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one, two, or three modifications, but no more than four modifications of GATAGTTA.
  • the encoded miR binding site is substantially identical (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% identical), to the miR in the host cell.
  • the encoded miR binding site comprises at least 1, 2, 3, 4, or 5 mismatches or no more than 6, 7, 8, 9, or 10 mismatches to a miR in the host cell.
  • the mismatched nucleotides are contiguous. In some embodiments, the mismatched nucleotides are non-contiguous. In some embodiments, the mismatched nucleotides occur outside the seed region-binding sequence of the miR binding site, such as at one or both ends of the miR binding site. In some embodiments, the encoded miR binding site is 100% identical to the miR in the host cell.
  • the nucleotide sequence encoding the miR binding site is substantially complimentary (e.g., at least 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% complementary), to the miR in the host cell.
  • the sequence complementary to the nucleotide sequence encoding the miR binding site comprises at least 1, 2, 3, 4, or 5 mismatches or no more than 6, 7, 8, 9, or 10 mismatches relative to the corresponding miR in the host cell.
  • the mismatched nucleotides are contiguous. In some embodiments, the mismatched nucleotides are non-contiguous.
  • the mismatched nucleotides occur outside the seed region-binding sequence of the miR binding site, such as at one or both ends of the miR binding site.
  • the encoded miR binding site is 100% complementary to the miR in the host cell.
  • the encoded miR binding site or the encoded miR binding site series is about 10 to about 125 nucleotides in length, e.g., about 10 to 50 nucleotides, 10 to 100 nucleotides, 50 to 100 nucleotides, 50 to 125 nucleotides, or 100 to 125 nucleotides in length.
  • an encoded miR binding site or the encoded miR binding site series is about 7 to about 28 nucleotides in length, e.g., about 8-28 nucleotides, 7-28 nucleotides, 8-18 nucleotides, 12-28 nucleotides.
  • a rniRNA e.g., a miR122, a miR142, a miR-1 , a miR183.
  • the encoded miR binding site is complementary (e.g., folly complementary or partially complementary ) to a miR expressed in liver or hepatocytes, such as miR122.
  • the encoded miR binding site or encoded miR binding site series comprises a miR122 binding site sequence.
  • the encoded miR122 binding site comprises the nucleotide sequence of ACAAACACCATTGTCACACTCCA (SEQ ID NO: 1865), or a nucleotide sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, at least 95%, at least 99%, or 100% sequence identity', or having at least one, two, three, four, five, six, or seven modifications but no more than ten modifications to SEQ ID NO: 1865. e.g., wherein the modification can result in a mismatch between the encoded miR binding site and the corresponding miRNA.
  • the viral genome comprises at least 3, 4.
  • tire encoded miR122 binding site e.g., an encoded miR122 binding site series
  • the encoded miR122 binding site series comprises the nucleotide sequence of: ACAAACACCATTGTCACACTCCACACAAACACCATTGTCACACTCCACACAAACACCATTGTCACACTCCACACAAACACCATTGTCACACTCCA (SEQ ID NO: 1866), or a nucleotide sequence having at least 50%, 55%, 60%, 65%, 70%, 75%.
  • At least two of the encoded miR122 binding sites are connected directly, e.g., without a spacer. In other embodiments, at least two of the encoded miR122 binding sites are separated by a spacer, e.g., 1. 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length, which is located between two or more consecutive encoded miR122 binding site sequences.
  • tire spacer is about 1 to 6 nucleotides or about 5 to 10 nucleotides, e.g., about 7-8 nucleotides or about 8 nucleotides, in length.
  • the spacer sequence comprises one or more of (i) GGAT; (ii) CACGTG; (iii) GCATGC, or a repeat of one or more of (i)-(iii).
  • the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one, two, or three modifications, but no more than four modifications of GATAGTTA.
  • the encoded miR binding site is complementary (e.g., folly or partially complementary) to a miR expressed in the heart.
  • the encoded miR binding site or encoded miR binding site series comprises a miR-1 binding site.
  • the encoded miR-1 binding site comprises the nucleotide sequence of ATACATACTTCTTTACATTCCA (SEQ ID NO: 5025), a nucleotide sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, at least 95%, at least 99%, or 100% sequence identity, or having at least one, two, force, four, five, six, or seven modifications but no more than ten modifications to SEQ ID NO: 5025, e.g., wherein the modification can result in a mismatch between the encoded miR binding site and the corresponding miRNA.
  • the viral genome comprises at least 2, 3, 4, or 5 copies of the encoded miR-1 binding site, e.g., an encoded miR-1 binding site series.
  • the at least 2, 3, 4, or 5 copies (e.g., 2 or 3 copies) of the encoded miR-1 binding site arc continuous (e.g., not separated by a spacer) or separated by a spacer.
  • the spacer is about 1 to 6 nucleotides or about 5 to 10 nucleotides, e.g., about 7-8 nucleotides or about 8 nucleotides, in length.
  • the spacer sequence comprises one or more of (i) GGAT; (ii) CACGTG; (iii) GCATGC, or a repeat of one or more of (i)-(iii) .
  • the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one, two, or three modifications, but no more than four modifications of GATAGTTA.
  • the encoded miR binding site is complementary (e.g., fully complementary or partially complementary) to a miR expressed in hematopoietic lineage, including immune cells (e.g., antigen presenting cells or APC. including dendritic cells (DCs), macrophages, and B-lymphocytes).
  • the encoded miR binding site is complementary (e.g., fully complementary or partially complementary) to a miR expressed in hematopoietic lineage comprises a nucleotide sequence disclosed, e.g., in US 2018/0066279, the contents of which are incorporated by reference herein in its entirety .
  • the encoded miR binding site or encoded miR binding site series comprises a miR-142-3p binding site sequence.
  • tire encoded miR-142-3p binding site comprises the nucleotide sequence of TCCATAAAGTAGGAAACACTACA (SEQ ID NO: 1869), a nucleotide sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, at least 95%, at least 99%, or 100% sequence identity, or having at least one, two, three, four, five, six, or seven modifications but no more than ten modifications to SEQ ID NO: 1842, e.g., wherein the modification can result in a mismatch between the encoded miR binding site and the corresponding miRNA.
  • the viral genome comprises at least 3, 4, or 5 copies of an encoded miR-142-3p binding site, e.g., an encoded miR-142-3p binding site series.
  • the at least 3, 4, or 5 copies (e.g., 4 copies) of the encoded miR-142-3p binding site are continuous (e.g., not separated by a spacer) or separated by a spacer.
  • the spacer is about 1 to 6 nucleotides or about 5 to 10 nucleotides, e.g., about 7-8 nucleotides or about 8 nucleotides, in length.
  • the spacer sequence comprises one or more of (i) GGAT; (ii) CACGTG; (iii) GCATGC, or a repeat of one or more of (i)-(iii) .
  • the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one, two, or three modifications, but no more than four modifications of GATAGTTA.
  • the encoded miR binding site is complementary’ (e.g., fully complementary or partially complementary) to a miR expressed in a DRG (dorsal root ganglion) neuron, e.g., a miR183, a miR182, and/or miR96 binding site.
  • the encoded miR binding site is complementary (e.g., fully complementary' or partially complementary ) to a miR expressed in expressed in a DRG neuron.
  • the encoded miR binding site comprises a nucleotide sequence disclosed, e.g., in W02020/132455, the contents of which are incorporated by reference herein in its entirety.
  • tire encoded miR binding site or encoded miR binding site series comprises a miR183 binding site sequence.
  • the encoded miR183 binding site comprises the nucleotide sequence of AGTGAATTCTACCAGTGCCATA (SEQ ID NO: 1847). or a nucleotide sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, at least 95%, at least 99%, or 100% sequence identity, or having at least one, two, three, four, five, six, or seven modifications but no more than ten modifications to SEQ ID NO: 1847, e.g., wherein the modification can result in a mismatch between the encoded miR binding site and the corresponding miRNA.
  • the sequence complementary (e g., fully complementary or partially complementary) to the seed sequence corresponds to the double underlined of the encoded miR- 183 binding site sequence.
  • the viral genome comprises at least comprises at least 3, 4, or 5 copies (e.g., 4 copies) of the encoded miR183 binding site, e.g. an encoded miR183 binding site.
  • the viral genome comprises at least comprises 4 copies of the encoded miR183 binding site, e.g. an encoded miR183 binding site comprising 4 copies of a miR183 binding site.
  • the at least 3. 4, or 5 copies (e.g., 4 copies) of the encoded miR183 binding site are continuous (e.g..
  • the spacer is about 1 to 6 nucleotides or about 5 to 10 nucleotides, e.g., about 7-8 nucleotides or about 8 nucleotides, in length.
  • the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one, two, or three modifications, but no more than four modifications of GATAGTTA.
  • the encoded miR183 binding site series comprises tire nucleotide sequence of SEQ ID NO: 1849, or a nucleotide sequence having at least 50%, 55%, 60%, 65%, 70%, 75%. 80%. 85%. 90%, at least 95%, at least 99%, or 100% sequence identity, or having at least one, two. three, four, five, six, or seven modifications but no more than ten modifications to SEQ ID NO: 1849.
  • tire encoded miR binding site or encoded miR binding site series comprises a miR182 binding site sequence.
  • the encoded miR182 binding site comprises, tire nucleotide sequence of AGTGTGAGTTCTACCATTGCCAAA (SEQ ID NO: 1867), a nucleotide sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, at least 95%, at least 99%, or 100% sequence identity, or having at least one, two, three, four, five, six, or seven modifications but no more than ten modifications to SEQ ID NO: 1867, e.g., wherein the modification can result in a mismatch between the encoded miR binding site and the corresponding miRNA.
  • the viral genome comprises at least 3, 4, or 5 copies of the encoded miR182 binding site, e.g., an encoded miR182 binding site series.
  • the at least 3, 4. or 5 copies (e.g., 4 copies) of the encoded miR182 binding site are continuous (e.g., not separated by a spacer) or separated by a spacer.
  • the spacer is about 1 to 6 nucleotides or about 5 to 10 nucleotides, e.g.. about 7-8 nucleotides or about 8 nucleotides, in length.
  • the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one, two, or three modifications, but no more than four modifications of GATAGTTA.
  • the encoded miR binding site or encoded miR binding site series comprises a miR96 binding site sequence.
  • the encoded miR96 binding site comprises the nucleotide sequence of AGCAAAAATGTGCTAGTGCCAAA (SEQ ID NO: 1868), a sequence having at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, at least 95%, at least 99%, or 100% sequence identity, or having at least one, two, three, four, five, six, or seven modifications but no more than ten modifications to SEQ ID NO: 1868, e.g., wherein the modification can result in a mismatch between the encoded miR binding site and the corresponding miRNA.
  • the viral genome comprises at least 3. 4, or 5 copies of the encoded miR96 binding site, e.g., an encoded miR96 binding site series.
  • the at least 3, 4, or 5 copies (e.g., 4 copies) of the encoded miR96 binding site are continuous (e.g., not separated by a spacer) or separated by a spacer.
  • the spacer is about 1 to 6 nucleotides or about 5 to 10 nucleotides, e.g., about 7-8 nucleotides or about 8 nucleotides, in length.
  • the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one, two, or three modifications, but no more than four modifications of GATAGTTA.
  • the encoded miR binding site series comprises a miR122 binding site, a miR142 binding site, a miR183 binding site, a miR182 binding site, a miR 96 binding site, or a combination thereof.
  • the encoded miR binding site series comprises at least 3, 4, or 5 copies of a miR122 binding site, a miR-1. a miR142 binding site, a miR183 binding site, a miR182 binding site, a miR 96 binding site, or a combination thereof.
  • at least two of the encoded miR binding sites are connected directly, e.g., without a spacer.
  • the spacer e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length, which is located between two or more consecutive encoded miR binding site sequences.
  • the spacer is at least about 5 to 10 nucleotides, e.g., about 7-8 nucleotides or about 8 nucleotides, in length.
  • the spacer sequence comprises one or more of (i) GGAT; (ii) CACGTG; (iii) GCATGC, or a repeat of one or more of (i)-(iii) .
  • the spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one, two, or three modifications, but no more than four modifications of GATAGTTA.
  • an encoded miR binding site comprises at least 3-5 copies (e.g., 4 copies) of a combination of at least two, three, four, five, or all of a miR122 binding site, a miR-1 a miR142 binding site, a miR183 binding site, a miR182 binding site, a miR96 binding site, wherein each of the miR binding sites within the series are continuous (e.g., not separated by a spacer) or separated by a spacer.
  • the spacer is about 1 to 6 nucleotides or about 5 to 10 nucleotides, e.g.. about 7-8 nucleotides or about 8 nucleotides, in length.
  • the spacer sequence comprises one or more of (i) GGAT; (ii) CACGTG; (iii) GCATGC, or a repeat of one or more of (i)-(iii).
  • tire spacer comprises the nucleotide sequence of GATAGTTA, or a nucleotide sequence having at least one, two, or three modifications, but no more than four modifications of GATAGTTA.
  • the viral genome of an AAV particle described herein comprises an element to improve packaging efficiency and expression, such as a filler or stuffer sequence.
  • filler or stuffer sequences include albumin and/or alpha- 1 antitrypsin. Any known viral, mammalian, or plant sequence may be manipulated for use as a filler sequence.
  • tire filler sequence may be from about 100-3500 nucleotides in length.
  • the stuffer sequence may have a length of about 100. 200, 300. 400, 500. 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400. 1500. 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 nucleotides.
  • Viral Genome Component Polyadenylation Sequence
  • the viral genome comprises a polyadenylation (poly A) sequence.
  • the viral genome of the AAV particle e.g., an AAV particle comprising an AAV capsid variant, described herein
  • the viral genome of the AAV particle comprises a polyadenylation sequence between the 3 ’ end of tire nucleotide sequence encoding the payload and the 5’ end of the 3’ITR.
  • the polyA sequence comprises the nucleotide sequence of SEQ ID NO: 4476, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto.
  • an AAV particle e.g., an AAV particle for the vectorized delivery of a siRNA, e.g., a MAPT targeting siRNA described herein, comprises a payload.
  • an AAV particle e.g., an AAV particle for the vectorized delivery of a siRNA described herein (e.g., a MAPT targeting siRNA)
  • the viral genome comprises a promoter operably linked to a nucleic acid comprising a transgene encoding a payload.
  • the payload comprises a siRNA or a modulatory polynucleotide comprising or encoding an siRNA duplex.
  • the present disclosure relates to a composition containing or comprising a nucleic acid sequence encoding a MAPT targeting siRNA or functional fragment or variants thereof and methods of administering the composition in vitro or in vivo in a subject, e.g., a humans and/or an animal model of disease, e.g., a disease related to expression of MAPT.
  • AAV particles of the present disclosure may comprise a nucleic acid sequence encoding at least one payload.
  • payload or payload region refers to one or more polynucleotides or polynucleotide regions encoded by or within a viral genome or an expression product of such polynucleotide or polynucleotide region, e.g. , a transgene encoding a siRNA duplex, a modulatory polynucleotide, or a gene editing system for inhibiting expression of MAPT, or fragment or variant thereof.
  • the payload may comprise any nucleic acid known in the art that is useful for tire expression (by supplementation of the MAPT siRNA or gene replacement using a modulatory nucleic acid) of the MAPT targeting siRNA in a target cell transduced or contacted with the AAV particle carrying the payload.
  • AAV particle viral genomes of the present disclosure may comprise a payload region, which when expressed, results in the silencing, suppression, and/or reduction of the MAPT gene expression, corresponding transcript expression, and/or protein production.
  • the present disclosure provides small interfering RNA (siRNA) duplexes (and modulatory polynucleotides comprising or encoding them) that target MAPT transcript to modulate, e.g., inhibit or silence MAPT gene expression, mRNA production, and/or protein production.
  • the MAPT gene is a wild type gene.
  • the MAPT gene comprises at least one, e.g., one or more mutations, e.g., a mutated MAPT gene.
  • the MAPT gene to be targeted by a siRNA duplex as described herein comprises a mutation that results in the production of a tau protein comprising one, two. or all of a mutation at position 272. 301, and/or 406, e.g.. G272V, P301L, and/or R406W.
  • the MAPT gene to be targeted by a siRNA described herein is provided in Table 3.
  • a siRNA for targeting MAPT described herein targets a MAPT gene comprising a nucleotide sequence provided in Table 3 or a fragment or variant thereof (e.g., the nucleotide sequence of any one of SEQ ID NOs: 3944-3951 or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identical thereto).
  • the siRNA for targeting MAPT as described herein modulates the level of a protein comprising the amino acid sequence of any one of SEQ ID Nos. 3936-3943, or a fragment or variant thereof (e.g., an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identical to SEQ ID NOs: 3936-3943).
  • modulatory polynucleotides may be used to treat a neurodegenerative disease, e.g., a tauopathy, e.g.. Alzheimer's disease (AD) and frontotemporal dementia (FTD).
  • a neurodegenerative disease e.g., a tauopathy, e.g.. Alzheimer's disease (AD) and frontotemporal dementia (FTD).
  • the tauopathy may be a neurodegenerative disease.
  • the tauopathy may be a non-neurodegenerative disease without neurodegeneration.
  • the tauopathy is a familial tauopathy (e g., genetic) or a sporadic tauopathy (e.g., idiopathic).
  • a modulatory polynucleotide described herein, e.g., an RNA or DNA molecule is used to treat epilepsy or Dravet syndrome (DS).
  • the modulatory polynucleotides may comprise a nucleic acid sequence encoding a siRNA molecule. In some embodiments, the modulatory polynucleotides may comprise a nucleic acid sequence encoding at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 siRNA molecules. In some embodiments the modulatory polynucleotide comprises a siRNA molecule, e.g., an siRNA molecule described herein. siRNA Molecules for Targeting MAPI
  • RNA interference (RNAi) agents e.g., a siRNA, that modulate (e.g., inhibit) expression of MAPT.
  • a siRNA molecule described herein modulates, reduces and/or silences, e.g., inhibits a MAPT gene, mRNA, and or protein expression.
  • a siRNA molecule described herein modulates, reduces, and/or silences, e.g., inhibits, MAPT transcript expression, gene expression and/or protein production in cortical neurons, thereby ameliorating symptoms of Alzheimer’s disease (AD) and/or frontotemporal dementia (FTD).
  • AD Alzheimer’s disease
  • FTD frontotemporal dementia
  • a siRNA molecule described herein modulates, reduces, and/or silences, e.g., inhibits. MAPT transcript expression, gene expression and/or protein production in interneurons and/or hippocampal neurons, thereby ameliorating symptoms of Dravet syndrome (DS).
  • the hippocampal neuron is a dentate gyrus granule cell neuron.
  • RNAi also known as post-transcriptional gene silencing (PTGS), quelling, or co-suppression
  • PTGS post-transcriptional gene silencing
  • the active components of RNAi are short/small double stranded RNAs (dsRNAs), called small interfering RNAs (siRNAs), that typically contain 15-30 nucleotides (e.g., 19 to 25, 19 to 24 or 19-21 nucleotides) and 2 nucleotide 3’ overhangs, and that match the nucleic acid sequence of the target gene.
  • dsRNAs short/small double stranded RNAs
  • siRNAs small interfering RNAs
  • These short RNA species may be naturally produced in vivo by Dicer-mediated cleavage of larger dsRNAs and they are functional in mammalian cells.
  • miRNAs Naturally expressed small RNA molecules, named microRNAs (miRNAs), elicit gene silencing by regulating the expression of mRNAs.
  • the miRNAs-containing RNA Induced Silencing Complex (RISC) targets mRNAs presenting a perfect sequence complementarity with nucleotides 2-7 in the 5’ region of the miRNA which is called the seed region, and other base pairs with its 3’ region.
  • miRNA-mediated downregulation of gene expression may be caused by cleavage of the target mRNAs, translational inhibition of tire target mRNAs, or rnRNA decay.
  • miRNA targeting sequences arc usually located in tire 3 ’ -UTR of the target mRNAs.
  • a single miRNA may target more than 100 transcripts from various genes, and one mRNA may be targeted by different miRNAs.
  • siRNA duplexes or dsRNA targeting a specific mRNA may be designed and synthesized in vitro and introduced into cells for activating RNAi processes (e.g., as described in Elbashir SM et al., Nature, 2001, 411, 494-498, the contents of which are hereby incorporated by reference in their entirety).
  • siRNA molecules may be introduced into cells to activate RNAi.
  • An exogenous siRNA duplex when it is introduced into cells, similar to the endogenous dsRNAs, can be assembled to form the RNA Induced Silencing Complex (RISC), a multiunit complex that interacts with RNA sequences that are complementary to one of the two strands of the siRNA duplex (i.e., the antisense strand).
  • RISC RNA Induced Silencing Complex
  • the sense strand (or passenger strand) of the siRNA is lost from the complex, while the antisense strand (or guide strand) of the siRNA is matched with its complementary RNA.
  • the targets of siRNA containing RISC complexes are mRNAs presenting a perfect sequence complementarity. Then, siRNA mediated gene silencing occurs by cleaving, releasing and degrading the target.
  • siRNA duplex comprised of a sense strand homologous to the target RNA transcript and an antisense strand that is complementary to the target RNA transcript offers much more advantage in terms of efficiency for target RNA destruction compared to the use of the single strand (ss)-siRNAs (e.g., antisense strand RNA or antisense oligonucleotides). In many cases, it requires higher concentration of the ss-siRNA to achieve the effective gene silencing potency of the corresponding duplex.
  • ss-siRNAs single strand
  • a vector genome may encode a pri-miRNA or pre- miRNA, which when expressed in tire target cells is processed via the cell’s endogenous pathway to a miRNA duplex. Once the miRNA duplex unwinds, the guide strand may bind to its complementary mRNA substrate and recruit the RNA-induced silencing complex, which leads to the cleavage of the substrate mRNA.
  • delivery of an AAV particle comprising a vector genome encoding an RNAi precursor (pre- or pri-miR), enters the processing pathway at a different step than would occur with direct administration of an shRNA or siRNA, for example.
  • Any of the foregoing molecules may be encoded by an AAV vector or vector genome.
  • a nucleic acid sequence encoding such siRNA molecules, or a single strand of the siRNA molecules is inserted into the vector genome of an AAV particle and introduced into cells, specifically neurons, including interneurons, and/or other surrounding cells in the central nervous system.
  • siRNA molecules e.g., siRNA duplexes or encoded dsRNA
  • the siRNA molecule is able to modulate, e.g., inhibit, expression of a wild type MAPT gene, mRNA, and/or protein.
  • the siRNA molecule is able to modulate, e.g.. inhibit, expression of a MAPT gene, mRNA, and/or protein comprising at least one mutation, e.g., a mutated MAPT gene, mRNA. and/or protein.
  • the mutation is a mutation associate with atauopathy, e.g., frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).
  • the MAPT is a human MAPT.
  • the MAPT sequence e.g., the MAPT sequence targeted by an siRNA described herein, comprises the nucleotide sequence of NM 001123066.4, which comprises the nucleotide sequence of: GCAGTCACCGCCACCCACCAGCTCCGGCACCAACAGCAGCGCCGCTGCCACCGCCCACCTTCTGCCGCCGCCACCACAGC CACCTTCTCCTCCTCCGCTGTCCTCTCCCGTCCTCGCCTCTGTCGACTATCAGGTGAACTTTGAACCAGGATGGCTGAGC CCCGCCAGGAGTTCGAAGTGATGGAAGATCACGCTGGGACGTACGGGTTGGGGGACAGGAAAGATCAGGGGGGCTACACC ATGCACCAAGACCAAGAGGGTGACACGGACGCTGGCCTGAAAGAATCTCCCCTGCAGACCCCCACTGAGGACGGATCTGA GGAACCGGGCTCTGAAACCTCTGATGCTAAGAGCACTCCAACAGCGGAAGATGTGACAGCACCCTTAGTGGATGAG CT
  • an siRNA molecule of the present disclosure comprises a sense strand and a complementary antisense strand in which both strands are hybridized together to form a duplex structure.
  • the antisense strand may have sufficient complementarity to the MAPT transcript sequence to direct target- specific RNAi to the target mRNA, e.g.. the siRNA molecule has a sequence sufficient to trigger the destruction of the target transcript by the RNAi machinery’ or process.
  • an siRNA molecule of the present disclosure comprises a sense strand and a corresponding antisense strand.
  • the antisense strand is complementary, e.g., substantially complementary or fully complementary to at least a portion of a MAPT gene, e.g., a MAPT gene as described in Table 3 or 19, or a variant thereof (e.g., a human MAPT).
  • the antisense strand is complementary, e.g., partially complementary or fully complementary, to a region of the MAPT transcript, e.g., a region between nucleotide 1 and 6850 on the MAPT transcript sequence, e.g., as described in Table 19.
  • the region of complementary comprises nucleotides 1-50, 50-100, 100-150, 150-200, 200-250. 250-300, 300-350, 350-400, 400-450, 450-500, 500-550, 550-600, 600- 650. 650-700, 700-750, 750-800, 800-850, 850-900.
  • the antisense strand sequence comprises a region of complementarity to the target sequence (e.g., a MAPT target), which is 15-30. 19-21, or 25-30 nucleotides in length, e.g., 15, 16, 17, 18, 19, 20. 21. 22, 23, 24, 25, 26, 27, 28, 29. or 30 nucleotides in length.
  • the antisense strand sequence is fully complementary to the target sequence (e.g., 100% complementary).
  • the antisense strand sequence is substantially complementary to the target sequence.
  • the antisense strand sequence comprises a region of complementarity to a portion of a the target sequence (e.g., a MAPT sequence provided in Table 3 or 19 or a variant thereof), e.g., a portion of at least 15, 16, 17, 18. 19, 20, or 21 contiguous nucleotides that comprises one, two. or three mismatches relative to the target sequence.
  • the antisense strand sequence is complementary to at least 15, 16, 17.
  • the antisense strand sequence is complementary to at least 15, 16, 17, 18, 19, 20, or 21, contiguous nucleotides with 0, 1, 2, or 3 mismatches to a portion of the target sequence present in an exon (e.g., an exon comprising nucleotides 1277 to 1332 of SEQ ID NO: 5024, an exon comprising nucleotides 1712-1977 of SEQ ID NO: 5024, or an exon comprising nucleotides 2266-6644 of SEQ ID NO: 5024) of a coding sequence of a MAPT rnRNA, e.g., a MAPT sequence of SEQ ID NO: 5024, e.g., a coding sequence comprising nucleotides 151 to 2481 of SEQ ID NO: 5024.
  • an exon e.g., an exon comprising nucleotides 1277 to 1332 of SEQ ID NO: 5024, an exon comprising nucleotides 1712-1977 of SEQ ID NO: 5024
  • the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides with 0, 1, 2, or 3 mismatches of the corresponding portion of a MAPT sequence, e.g., a MAPT sequence provided in Table 3 or 19, or a variant thereof.
  • the sense strand sequence or a portion thereof corresponds to positions 1300-1317, 1305-1322, 1860-1877, 2279-2297 ⁇ 2286- 2303, 2402-2419, 2581-2958, 2584-2601, 2633-2650, or 2634-2653 of SEQ ID NO: 5024.
  • the sense strand sequence comprises a nucleotide sequence comprising at least 15, 16, 17, 18, 19, 20, or 21, contiguous nucleotides with 0, 1, 2, or 3 mismatches of tire corresponding portion of an exon (e.g., an exon comprising nucleotides 1277 to 1332 of SEQ ID NO: 5024, an exon comprising nucleotides 1712-1977 of SEQ ID NO: 5024, or an exon comprising nucleotides 2266-6644 of SEQ ID NO: 5024) of a coding sequence of a MAPT mRNA, e g., a MAPT sequence of SEQ ID NO: 5024, e.g., a coding sequence comprising nucleotides 151 to 2481 of SEQ ID NO: 5024.
  • an exon e.g., an exon comprising nucleotides 1277 to 1332 of SEQ ID NO: 5024, an exon comprising nucleotides 1712-1977 of SEQ ID NO: 50
  • the sense strand sequence comprises at least 15, 16, 17, or 18 contiguous nucleotides with 0, 1, 2, or 3 mismatches from nucleotides 1300-1317, 1305-1322, 1860-1877, 2279-2297, 2286-2303, 2402-2419, 2581-2958, 2584-2601. 2633-2650, or 2634-2653 of SEQ ID NO: 5024.
  • the sense strand sequence and the antisense strand sequence of an siRNA described herein comprise a region of complementarity, which is 15-30, 19-21, or 25-30 nucleotides in length, e.g., 17, 18, 20, 21, 22, 25, or 30 nucleotides in length.
  • the sense strand, antisense strand, or both comprise at least 15-30, 19-21, or 25-30 nucleotides in length, e.g., 17, 18, 20, 21, 22, 25, or 30 nucleotides in length.
  • tire sense strand, antisense strand, or both tire sense strand comprise one or two nucleotide overhangs, e.g..
  • the sense strand and the antisense strand comprise one mismatch.
  • the antisense strand sequence comprises one mismatch with the target sequence.
  • the siRNA molecules of the present disclosure can be synthetic RNA duplexes comprising about 19 nucleotides to about 25 nucleotides, and two overhanging nucleotides at the 3'- end.
  • the siRNA molecules may be unmodified RNA molecules.
  • the siRNA molecules may contain at least one modified nucleotide, such as base, sugar or backbone modifications.
  • the overhanging nucleotides at the 3 ’-end of each of the sense and the antisense strand is a dTdT overhang.
  • the sense strand, antisense strand, or both the sense strand and the antisense strand does not comprise a dTdT overhang.
  • the siRNA molecule comprises an antisense (e.g., guide) strand sequence.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the antisense strand sequences provided in Tables 4, 5, 9A, or 9B.
  • the antisense sequence comprises the nucleotide sequence of any one of the antisense strand sequences provided in Tables 4, 5, 9A.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, or more than 19 consecutive nucleotides of a nucleotide sequence of any one of the antisense strand sequences provided in Tables 4, 5, 9A, or 9B.
  • the antisense sequence comprises nucleotides 1 to 19, 1 to 18, 1 to 17, 1 to 16, 2 to 19, or 2 to 18, 2 to 17 of any one of the antisense strand sequences provided in Tables 4, 5, 9A, or 9B.
  • the antisense sequence may comprise a dTdT overhang, e.g..
  • the antisense sequence does not comprise a dTdT overhang, e.g., does not comprise a dTdT overhang at the 3’ end of the sequence.
  • the antisense strand sequence is a DNA sequence (e.g., comprises T in place of U in any one of the sequences provided in Tables 4 and 5).
  • the antisense strand sequence is an RNA sequence (e.g., comprises U in place of T in any one of the sequences provided in Table 9 A or 9B).
  • the siRNA molecule comprises a sense (e.g., passenger) strand sequence.
  • the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from any one of the sense strand sequences provided in Tables 4, 5, 9A, or 9B.
  • the sense sequence comprises the nucleotide sequence of anyone of the sense strand sequences provided in Tables 4, 5, 9A, or 9B, or a nucleotide sequence 70%, 80%. 85%, 90%, 95% identical thereto.
  • the sense strand sequence comprises at least 15. 16. 17, 18, 19.
  • the sense sequence comprises nucleotides 1 to 19, 1 to 18, 1 to 17, 1 to 162 to 19, or 2 to 18, 2 to 17 of any one of the sense strand sequences provided in Tables 4, 5, 9A, or 9B.
  • the sense sequence may comprise a dTdT overhang, e.g. at the 3’ end of the sense strand sequence.
  • the sense sequence does not comprise a dTdT overhang, e.g., does not comprise the dTdT overhang at tire 3’ end of the sequence.
  • the sense strand sequence is a DNA sequence (e.g., comprises T in place of U in any one of the sequences provided in Tables 4 and 5). In some embodiments, the sense strand sequence is an RNA sequence (e.g., comprises U in place of T in any one of the sequences provided in Table 9A or 9B).
  • the siRNA comprises an antisense strand sequence comprising a nucleotide sequence comprising at least 15. 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by no more than 3, 2, 1. or 0 nucleotides from the antisense strand sequences provided in Tables 4, 5. 9A. or 9B; and a sense strand sequence comprising a nucleotide sequence comprising at least 15.
  • the siRNA molecules of the present disclosure may comprise a siRNA duplex as described in Table 4. 5 9A, or 9B, or a variant, e.g., functional variant, thereof.
  • the dTdT nucleotides of the sense strand and/or the antisense strand of the siRNA provided in Table 4 or herein may be replaced with any two nucleotides (e.g., UU, UC, AA, AG, AC, etc.).
  • the dTdT nucleotides of the sense strand and/or the antisense strand of Table 4 or provided herein may be replaced with a single nucleotide (e.g., U, A, C, or G).
  • Table 5 Exemplary sense and antisense strand sequence for targeting MAPT
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4700.
  • the siRNA comprises a sense strand sequence comprising at least 15. 16. 17. 18, or 19 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4502-4505.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4700 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4502-4505.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4920.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18. 19. 20. or 21 contiguous nucleotides differing by 3, 2, 1. or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938, 4958, 4978, or 4998.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4920 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4918, 4938, 4958, 4978. or 4998.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4920. In some embodiments, the antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4920. In some embodiments, the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4920.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4918. In some embodiments, the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4918. In some embodiments, the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4918. In some embodiments, the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2.
  • the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4918.
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand comprises the nucleotide sequence of SEQ ID NO: 4918.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4919. In some embodiments, the nucleotide sequence encoding the antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4919. In some embodiments, the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919.
  • tire nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4917. In some embodiments, the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4917. In some embodiments, the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4917.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4919 and the nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4917.
  • the nucleotide sequence encoding tire antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4919; and the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4917.
  • the nucleotide sequence encoding the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 4919; and the nucleotide sequence encoding the sense strand comprises tire nucleotide sequence of SEQ ID NO: 4917.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16. 17. 18. 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4920.
  • the antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4920.
  • the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4920.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from tire nucleotide sequence of SEQ ID NO: 4978. In some embodiments, the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4978. In some embodiments, the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4978.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4920; and tire sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4978.
  • the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4920; and the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4978.
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4920; and the sense strand comprises the nucleotide sequence of SEQ ID NO: 4978.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16. 17. 18. 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4919. In some embodiments, the nucleotide sequence encoding the antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4919. In some embodiments, the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4919. In some embodiments, the nucleotide sequence encoding tire sense strand sequence comprises at least 15, 16, 17, 18, 19, 20.
  • nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4977. In some embodiments, the nucleotide sequence encoding tire sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4977.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4919; and the nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4977.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4919; and the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4977.
  • the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4919; and the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4977.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4697.
  • the siRNA comprises a sense strand sequence comprising at least 15. 16. 17, 18, or 19 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4495-4499.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4697 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4495-4499.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4908.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4906, 4926. 4946, 4966, 4986, or 5006.
  • tire antisense strand sequence comprises at least 15, 16, 17, 18, 19. 20.
  • nucleotide sequence of SEQ ID NO: 4908 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4906, 4926, 4946, 4966, 4986, or 5006.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16. 17. 18, 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4908. In some embodiments, the antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4908. In some embodiments, the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4908.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4906. In some embodiments, the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4906. In some embodiments, the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4906.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4908; and tire sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4906.
  • the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4906.
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908; and the sense strand comprises the nucleotide sequence of SEQ ID NO: 4906.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16. 17. 18, 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4907.
  • the nucleotide sequence encoding tire antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4907.
  • the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907.
  • the nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4905. In some embodiments, the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4905. In some embodiments, the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4905.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4907; and the nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19. 20. or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4905.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4907; and the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4905.
  • the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4907: and the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4905.
  • tire siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4908.
  • the antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4908.
  • the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4908.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4966. In some embodiments, the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4966. In some embodiments, the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4966. In some embodiments, the antisense strand sequence comprises at least 15.
  • tire antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4908; and the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4966.
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4908: and the sense strand comprises the nucleotide sequence of SEQ ID NO: 4966.
  • tire nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4907. In some embodiments, the nucleotide sequence encoding tire antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4907. In some embodiments, the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4907.
  • tire nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4965. In some embodiments, the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4965. In some embodiments, the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4965.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4907; and the nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19. 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4965.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4907; and the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4965.
  • the nucleotide sequence encoding the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 4907; and the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4965.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4690. In some embodiments, the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4480-4484.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4690 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4480-4484.
  • tire siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16. 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4924.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2. 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4924 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4922, 4942, 4962, 4982, 5002, or 5022.
  • tire siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4924.
  • the antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4924.
  • the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4924.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4922. In some embodiments, the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4922. In some embodiments, the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4922. In some embodiments, the antisense strand sequence comprises at least 15. 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2.
  • the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4922.
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand comprises the nucleotide sequence of SEQ ID NO: 4922.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4923. In some embodiments, the nucleotide sequence encoding the antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4923. In some embodiments, the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923.
  • tire nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4921. In some embodiments, the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4921. In some embodiments, the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4921.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4923; and the nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4921.
  • the nucleotide sequence encoding tire antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4923; and the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4921.
  • the nucleotide sequence encoding the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 4923; and the nucleotide sequence encoding the sense strand comprises tire nucleotide sequence of SEQ ID NO: 4921.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16. 17. 18. 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4924.
  • the antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4924.
  • the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4924.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from tire nucleotide sequence of SEQ ID NO: 4982. In some embodiments, the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4982. In some embodiments, the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4982.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4924; and tire sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4982.
  • the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4924; and the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4982.
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4924; and the sense strand comprises the nucleotide sequence of SEQ ID NO: 4982.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16. 17. 18. 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4923. In some embodiments, the nucleotide sequence encoding the antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4923. In some embodiments, the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4923. In some embodiments, the nucleotide sequence encoding tire sense strand sequence comprises at least 15, 16, 17, 18, 19, 20.
  • nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4981. In some embodiments, the nucleotide sequence encoding tire sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4981.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4923; and the nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4981.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4923; and the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4981.
  • the nucleotide sequence encoding the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4923; and the nucleotide sequence encoding the sense strand comprises the nucleotide sequence of SEQ ID NO: 4981.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4694. In some embodiments, the siRNA comprises a sense strand sequence comprising at least 15. 16. 17, 18, or 19 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4492. 5052. 5062, 5068, or 5072.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4694 and tire sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4492, 5052. 5062, 5068, or 5072.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 5057.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5054, 5060. 5064, 5066, 5070, or 5074.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3. 2. 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 5057; and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5054, 5060, 5064, 5066, 5070, or 5074.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16. 17. 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4691 .
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4485-4489.
  • tire antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4691 and the sense strand sequence comprises at least 15. 16. 17, 18, or 19 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4485-4489.
  • tire siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4916.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19. 20. or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994, or 5014.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4916 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4914, 4934, 4954, 4974, 4994. or 5014.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4701.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4506-4510.
  • the antisense strand sequence comprises at least 15. 16. 17, 18, or 19 contiguous nucleotides differing by 3. 2.
  • nucleotide sequence of SEQ ID NO: 4701 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4506-4510.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16. 17. 18, 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4912.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4912 and the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4910, 4930, 4950, 4970, 4990, or 5010.
  • tire siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16. 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4912. In some embodiments, the antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4912. In some embodiments, the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4912.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4970. In some embodiments, the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4970. In some embodiments, the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4970.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4912; and tire sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4970.
  • tire antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4912; and the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4970.
  • the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4912: and the sense strand comprises the nucleotide sequence of SEQ ID NO: 4970.
  • tire nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4911. In some embodiments, the nucleotide sequence encoding tire antisense strand comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4911. In some embodiments, the nucleotide sequence encoding the antisense strand comprises the nucleotide sequence of SEQ ID NO: 4911.
  • tire nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4969. In some embodiments, the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4969. In some embodiments, the nucleotide sequence encoding the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 4969.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4911; and the nucleotide sequence encoding the sense strand sequence comprises at least 15, 16, 17, 18, 19. 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4969.
  • the nucleotide sequence encoding the antisense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4911; and the nucleotide sequence encoding the sense strand sequence comprises at least 20 or 21 contiguous nucleotides of SEQ ID NO: 4969.
  • the nucleotide sequence encoding the antisense strand sequence comprises tire nucleotide sequence of SEQ ID NO: 4911; and the nucleotide sequence encoding tire sense strand comprises the nucleotide sequence of SEQ ID NO: 4969.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4687.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4477, 5082. 5086, 5090, 5094, or 5086.
  • the antisense strand sequence comprises at least 15. 16. 17, 18, or 19 contiguous nucleotides differing by 3.
  • nucleotide sequence of SEQ ID NO: 4687 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4477, 5082, 5086, 5090, 5094, or 5086.
  • tire siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16. 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 5080.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18. 19. 20. or 21 contiguous nucleotides differing by 3, 2, 1. or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5077, 5084, 5088, 5092, 5096, or 5098.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 5080; and the sense strand sequence comprises at least 15. 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5077, 5084, 5088, 5092, 5096, or 5098.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4712. In some embodiments, the siRNA comprises a sense strand sequence comprising at least 15. 16. 17, 18, or 19 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4521.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4712 and tire sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4521.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4696.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4494, 5106. 5110, 5114, or 5118.
  • the antisense strand sequence comprises at least 15. 16. 17, 18, or 19 contiguous nucleotides differing by 3.
  • nucleotide sequence of SEQ ID NO: 4696 and the sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4494, 5106, 5110, 5114, or 5118.
  • tire siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16. 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 5104.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5101, 5108, 5112, 5116, 5120, or 5122.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 5104; and the sense strand sequence comprises at least 15. 16. 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5101, 5108, 51 12, 5116, 5120, or 5122.
  • tire siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4718.
  • the siRNA comprises a sense strand sequence comprising at least 15. 16. 17. 18, or 19 contiguous nucleotides differing by 3. 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4527, 5130, 5134, 5138, or 5142.
  • the antisense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 4718 and tire sense strand sequence comprises at least 15, 16, 17, 18, or 19 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 4527. 5130. 5134, 5138, or 5142.
  • the siRNA for targeting MAPT comprises an antisense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of SEQ ID NO: 5128.
  • the siRNA comprises a sense strand sequence comprising at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5125, 5132. 5136, 5140, 5144, or 5146.
  • the antisense strand sequence comprises at least 15.
  • the sense strand sequence comprises at least 15, 16, 17, 18, 19, 20, or 21 contiguous nucleotides differing by 3, 2, 1, or 0 nucleotides from the nucleotide sequence of any one of SEQ ID NOs: 5125, 5132, 5136, 5140, 5144, or 5146.
  • the siRNA molecule is screened for tire ability to inhibit tau (MAPT) expression in a cell.
  • the cell is a HEK293 cell.
  • the cell is a human tau transgenic primary neuron and/or astrocyte-
  • the cell is a frontotemporal lobar degeneration (FTLD) patient fibroblast.
  • FTLD frontotemporal lobar degeneration
  • naive neuronal SK-N-AS cells monkey cell lines (CYN0M-K1, FRlrK-4, or LLC-MK2), primary neuron and astrocyte cultures from htau mice, frontotemporal lobar degeneration (FTLD)-tau patient induced pluripotent stem cells (iPSCs).
  • FTLD frontotemporal lobar degeneration
  • iPSCs patient induced pluripotent stem cells
  • FTLD-tau patient fibroblasts nervous system cells derived from multiple affected or at-risk donors (with and without MAPT mutations), FTLD-tau patient lymphoblasts, and human neural stem cells bearing homozygous or heterozygous mutations in MAPT (e.g., P301L, R406W, V337M) that may be introduced using CRISPR-Cas9 gene editing technology.
  • Tire screened siRNA duplex may be selected from any of the siRNA duplexes presented in Table 4 or 5 of the present disclosure.
  • the siRNA molecules of the present disclosure can be encoded by a vector, e.g., plasmid vector, a viral genome (e.g., an AAV viral genome), or another nucleic acid expression vector for delivery to a cell.
  • a siRNA molecule is encoded by a viral genome of an AAV particle.
  • DNA expression plasmids can be used to stably express the siRNA duplexes or dsRNA of the present disclosure in cells and achieve long-term inhibition of the target gene expression.
  • the sense and antisense strands of a siRNA duplex are typically linked by a short spacer sequence leading to the expression of a stem-loop structure termed short hairpin RNA (shRNA).
  • shRNA short hairpin RNA
  • the hairpin is recognized and cleaved by Dicer, thus generating mature siRNA molecules.
  • the sense and antisense strands of a siRNA duplex may be linked by a short spacer sequence, which may optionally be linked to additional flanking sequence, leading to the expression of a flanking arm-stem-loop structure termed primary microRNA (pri-miRNA).
  • pri-miRNA flanking arm-stem-loop structure
  • the pri-miRNA may be recognized and cleaved by Drosha and Dicer, and thus generate mature siRNA molecules.
  • Tire expression of MAPT may be assessed based on the level of expression of MAPT mRNA or MAPT protein.
  • the expression of MAPT e.g., MAPT mRNA
  • the siRNA duplexes or encoded dsRNA of the present disclosure suppress (or degrade) the target mRNA in a cell, e.g., a neuron (e.g., a cortical neuron) or a glial cell.
  • a neuron e.g., a cortical neuron
  • a glial cell e.g., a glial cell.
  • siRNA molecules are designed and tested for their ability to reduce MAPT transcript levels in cultured cells.
  • Such siRNA molecules may form a duplex such as, but not limited to, any of the sequences listed in Tables 4, 5, 9 A, or 9B.
  • the siRNA molecules comprise a miRNA seed match for the target (e.g., MAPT transcript) located in the guide strand.
  • the siRNA molecules comprise a miRNA seed match for the target (e.g., MAPT transcript) located in the passenger strand.
  • the siRNA duplexes or encoded dsRNA targeting MAPT transcript do not comprise a seed match for the target (e.g., MAPT transcript) located in the guide or passenger strand.
  • the siRNA duplex is designed so there is no miRNA seed match for the sense or antisense sequence to non- MAPT sequences.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a siRNA duplex targeting a MAPT gene, mRNA, or protein, and a pharmaceutically acceptable carrier.
  • the siRNA duplex is encoded by a viral genome and/or modulatory polynucleotide.
  • an AAV particle comprises the viral genome and an AAV capsid protein, e.g., an AAV capsid variant described herein.

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EP23855770.6A 2022-12-29 2023-12-28 Zusammensetzungen und verfahren zur regulierung von mapt Pending EP4642911A2 (de)

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WO2024145474A2 (en) 2024-07-04
AU2023417630A1 (en) 2025-05-15
CA3272944A1 (en) 2024-07-04
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